Статті в журналах: "MonoMac and DCML syndrome"

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Kazenwadel, Jan, Genevieve A. Secker, Yajuan J. Liu, Jill A. Rosenfeld, Robert S. Wildin, Jennifer Cuellar-Rodriguez, Amy P. Hsu, et al. "Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature." Blood 119, no. 5 (February 2, 2012): 1283–91. http://dx.doi.org/10.1182/blood-2011-08-374363.

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Abstract Recent work has established that heterozygous germline GATA2 mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), “MonoMAC” syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs*53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or “MonoMAC” syndrome patients with GATA2 deletions and one with a frameshift mutation also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurring us to investigate whether GATA2 plays a role in the lymphatic vasculature. We demonstrate here that GATA2 protein is present at high levels in lymphatic vessel valves and that GATA2 controls the expression of genes important for programming lymphatic valve development. Our data expand the phenotypes associated with germline GATA2 mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of GATA2, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development.

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Wang, Weixin, Meghan Corrigan-Cummins, Donald C. Vinh, Amy P. Hsu, Dennis D. Hickstein, Steven M. Holland, and Katherine R. Calvo. "MCL-1 and Mir-181c in GATA2 Mutation Associated Monomac and Familial Myelodysplastic Syndrome." Blood 120, no. 21 (November 16, 2012): 3807. http://dx.doi.org/10.1182/blood.v120.21.3807.3807.

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Abstract Abstract 3807 Background: Somatic and germline mutations in GATA2 were recently identified in patients diagnosed with MonoMAC, the hallmarks of which include mono cytopenia, B-cell and NK-cell lymphopenia, susceptibility to opportunistic infections (e.g. MAC), and a strong propensity to develop hypocellular MDS/AML or CMML. GATA2 mutations were also recently identified in other related disorders: Emberger syndrome (primary lymphedema with myelodysplasia), Familial MDS/AML, and DCML (Dendritic Cell, Monocytes, Lymphoid Deficiency). Family members with GATA2 mutations show variable penetrance and expressivity indicating that other factors may be required for development of disease and phenotype. GATA2 mutations are thought to result in loss of function or haploinsufficiency, but the precise mechanism for the development of cytopenias, immunodeficiency, and susceptibility to MDS remains to be elucidated. MicroRNA (miR) represents a unique mechanism of post-transcriptional gene regulation. In this study we generated microRNA profiles of patient derived MonoMAC cell lines followed by functional studies to identify aberrant miRs and their targets, which could potentially cooperate with GATA2 deficiency in generating hematologic disease. Inducible deletion of Myeloid Leukemia Cell 1 (Mcl1), a member of the Bcl2 family, in mice results in the loss of hematopoietic stem cells (HSCs) and progenitors, and in development of cytopenias. Design: RNA was isolated from EBV-immortalized B cells of 10 healthy controls and 13 MonoMAC patients with MDS and defined mutations in GATA2. microRNA expression profiles were generated using the Agilent high density human microRNA array. Array data were normalized to the data point of 75th percentile signal strength and to a set of spike-in and control probes. The differences between the means of experimental groups were analyzed by Mann-Whitney rank sum test. The miRs with significant p values (p≤ 0.05) and fold change (≥ 2-fold) in both normalization methods were selected for further analysis. TargetScan was utilized to predict the mRNA targets of aberrantly expressed miRs. miR targets were validated by functional studies in the Ly8 cell line. Results: Eight miRs were significantly differentially expressed (≥ 2-fold; p ≤ 0.05) as determined by microRNA microarray profiles. Six miRs showed increased expression in monoMAC cell lines compared to controls (miR-9, −181a-2–3p, −181c, −181c-3p, −486–3p, −582–5p) while two miRs showed significantly decreased expression (miR-223, −424–3p). Among the differentially expressed miRs that were validated by quantitative RT-PCR was miR-181c, which demonstrated a 2.2 fold increase in expression in MonoMAC cell lines (p = 0.013). Among the target transcripts potentially regulated by miR-181c, MCL1 expression was significantly decreased (2 fold; p = 0.018) in monoMAC cell lines in comparison to control cell lines. Transient transfection of miR-181c in Ly8 cells resulted in 40% decrease of MCL1 mRNA level, suggesting that miR-181c negatively regulates MCL1 in MonoMAC. Conclusions: These findings indicate that MonoMAC/GATA2 deficiency is associated with significantly decreased expression of MCL1 possibly through negative regulation involving miR-181c. Deletion of Mcl1 is known to cause apoptosis, loss of HSCs, and cytopenias in murine studies. Thus, down-regulation of MCL1 seen in MonoMAC/GATA2 deficiency may similarly favor unregulated apoptosis and the depletion of hematopoietic progenitors resulting in cytopenias, immunodeficiency, and risk of MDS/AML. Disclosures: No relevant conflicts of interest to declare.

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Hsu, Amy, M. Monica Gramatges, Christopher Williams, Brian Yang Merritt, M. Tarek Elghetany, Steven M. Holland, and Alison Bertuch. "GATA2 Mutations In Nonsyndromic Pediatric Myelodysplastic Syndrome." Blood 122, no. 21 (November 15, 2013): 2778. http://dx.doi.org/10.1182/blood.v122.21.2778.2778.

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Abstract Myelodysplastic syndrome (MDS) is rare in children. Certain inherited bone marrow failure syndromes (IBMFS), such as Fanconi anemia, severe congenital neutropenia and Shwachman Diamond syndrome, markedly increase the risk of MDS during childhood. However, the genetic factor(s) underlying sporadic pediatric MDS are unknown. Germline mutations in GATA2, a hematopoietic transcription factor, explain four MDS-predisposing conditions: monocytopenia and mycobacterial infection (MonoMAC); dendritic cell, monocyte, B and NK cell lymphoid deficiency (DCML); primary lymphedema with myelodysplasia progressing to acute myeloid leukemia (Emberger syndrome); and a subset of familial MDS. Cases of pediatric MDS have been observed in some of the reported pedigrees. In addition, three individuals have been reported with large, de novo deletions encompassing GATA2 and surrounding genes and manifesting developmental delay, intellectual disability and dysmorphic features alongside their hematologic abnormalities. We identified a novel GATA2 splice site variant (c.1018-2A>C) in a teenager with MDS, WHO classification refractory cytopenia of childhood (RCC). Although he was found to have monocytopenia and B and NK cell deficiencies, he had no history of infections associated with MonoMAC or pertinent family history. We, therefore, hypothesized that mutations in GATA2 might be present in additional cases of pediatric MDS that were neither associated with an IBMFS nor relevant personal or family history. Two Baylor College of Medicine biology studies open to children with hematologic disease were queried for patients with the diagnosis of MDS. Exclusion criteria included treatment-related MDS, diagnosis of an IBMFS, prior diagnosis of severe aplastic anemia or infections suspicious for MonoMAC or DCML, and known or suspected family history of a GATA2-associated disorder. Cases lacking a pre-hematopoietic stem cell transplantation (HSCT) tissue sample available for study were also excluded. In addition to the patient described above, six children were identified who met eligibility criteria. DNA was isolated from banked peripheral blood or bone marrow cells and GATA2 sequencing performed, including upstream and intronic regulatory regions. Array comparative genomic hybridization was also performed on one sample that lacked GATA2 sequence variants, but was notable for complete absence of heterozygosity (AOH), including 6 polymorphic sites with minor allele frequencies of 0.20 or greater. Pertinent clinical and laboratory features were extracted by medical record review blinded to GATA2 status. We found heterozygous GATA2 mutations in three of the six additional patient samples. Thus, four of this seven patient, pediatric MDS cohort had mutated GATA2. Two of the newly identified mutations were splice site variants: a previously described c.1018-1G>A and a novel variant altering the exon 7 splice site acceptor (c.1114-1G>C). The third mutation was a de novo 3.1-3.3 Mb deletion encompassing the entire GATA2 locus and contiguous genes, and was established to be germline by analysis of skin fibroblasts. Notably, the patient had normal neurocognitive development and was without dysmorphic features. Their ages of presentation were 5, 9, 12 and 15 years. With the exception of the initial case, peripheral blood T and B cell phenotyping was not obtained prior to HSCT. Monocytopenia of less than 200/µL was present in five of seven patients, three of whom had a GATA2 mutation. All four GATA2 mutation cases had RCC and three of the four had monosomy 7 at diagnosis. In contrast, the three cases lacking GATA2 mutation presented with the MDS classification refractory anemia with excess blasts (RAEB-2), with either a normal karyotype, complex karyotypic changes or chromosome 13.q12q14 deletion. GATA2 mutation may explain a significant portion of sporadic, seemingly nonsyndromic pediatric MDS, particularly cases with monosomy 7. Evaluation of larger cohorts is warranted to ascertain the true prevalence. Although this cohort is small, we recommend GATA2 sequencing be performed as part of the initial evaluation of pediatric MDS as the identification of a germline mutation has critical implications for related donor selection and genetic counseling. AOH in GATA2 sequencing should prompt deletion analysis, even in cases without infections, dysmorphic features or neurocognitive impairment. Disclosures: No relevant conflicts of interest to declare.

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Shiba, Norio, Kentarou Ohki, Myoung-ja Park, Souichi Adachi, Masao Kobayashi, Akitoshi Kinoshita, Manabu Sotomatsu, et al. "GATA2 Mutations in Pediatric Acute Myeloid Leukemia: A Study of the Japanese Childhood AML Cooperative Study Group." Blood 120, no. 21 (November 16, 2012): 2536. http://dx.doi.org/10.1182/blood.v120.21.2536.2536.

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Abstract Abstract 2536 Background Acute myeloid leukemia (AML) is a complex disease caused by mutations, epigenetic modifications, and deregulated expression of genes leading to increased proliferation and decreased differentiation of hematopoietic progenitor cells. Although many important molecular markers have already been discovered in AML, no known prognosis-associated cytogenetic aberrations or mutations were detectable in a subset of AML patients. In this regard, recent reports of somatic mutations affecting the C-terminal zinc finger (ZF) 2 of GATA2 are intriguing, because these GATA2 mutations were associated with the progression of chronic myeloid leukemia, whereas hereditary ZF2 of GATA2 mutations predispose to AML and myelodysplastic syndrome. GATA2 mutations were also reported as a predisposing gene of the monocytopenia, mycobacterial infection (MonoMAC) syndrome and the dendritic cell, monoctye, B and NK lymphoid deficiency (DCML) syndrome. GATA2 belongs to a family of zinc finger transcription factors, and is important for hematopoietic stem cell proliferation and normal megakaryocytic development. These findings prompted us to search for possible GATA2 mutations in pediatric AML. Methods To explore the frequency and clinical impact of GATA2 mutations, we examined 157 Japanese pediatric AML patients, including 13 with FAB-M3 and 10 with Down syndrome (DS) who were treated on different treatment protocol, by PCR following direct sequencing. As GATA2 mutations thus far reported almost exclusively involved exons 4–6 that encode zinc finger 1 and 2 domain, we confined our analysis to these exons. Results GATA2 missense mutations were found in 7 out of 157 patients (4.5%). Notably, All of GATA2 mutations were located in ZF2 in this study, although almost all of GATA2 mutations in adult AML were located in ZF1. Wild type GATA2 were found in 3 of 3 AML patients with GATA2 mutation. The other 4 patients had no history of Mono MAC syndrome, suggesting that these mutations were acquired. The zinc finger region of GATA2 is required for binding to promyelocytic leukemia zinc finger (PLZF) protein can interact with GATA2 and can modify its transactivation capacity. Interestingly, 2 GATA2 mutations were found in FAB-M3 in this study, GATA2 mutations also may be associated with acute promyelocytic leukemia. Clinical and molecular features between patients with and without GATA2 mutations were not significantly different in the clinical parameters (WBC, age, sex, etc.), and the outcome of GATA2 mutation positive patients was not poor when compared to GATA2 mutation negative patients: Two of the 7 patients received allogeneic-stem cell transplantation (Allo-SCT) and one of them died of gastrointestinal hemorrhage after SCT. The other 5 patients who did not receive the SCT were still alive. Conclusion GATA2 is a new predisposition gene for pediatric AML and shows functional changes caused by mutations within a highly conserved threonine repeat located in ZF2. Interestingly, MonoMAC and DCML syndromes were not observed in de novo AML patients with GATA2 mutations. Although further investigation is needed, our results indicated that GATA2 mutations were associated with a favorable outcome in pediatric AML. Most of the patients with GATA2 mutations have been classified into an intermediate risk group in our study, however, their favorable outcome suggests that less aggressive treatment strategy without SCT might be appropriate for AML patients carrying GATA2 mutations. Disclosures: No relevant conflicts of interest to declare.

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Townsley, Danielle M., Amy Hsu, Bogdan Dumitriu, Steven M. Holland, and Neal S. Young. "Regulatory Mutations in GATA2 Associated with Aplastic Anemia." Blood 120, no. 21 (November 16, 2012): 3488. http://dx.doi.org/10.1182/blood.v120.21.3488.3488.

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Abstract Abstract 3488 Germline heterozygous mutations in GATA2 have been reported to cause familial myelodysplasia–acute myeloid leukemia (MDS/AML), monocytopenia and mycobacterial infection (monoMAC syndrome), dendritic cell, myeloid and NK cell lymphopenia (DCML), and Emberger syndrome (lymphedema and MDS). GATA2 is a zinc finger transcription factor that plays a crucial role in regulating growth of hematopoietic progenitors. In some pedigrees, patients or family members have manifestations of bone marrow failure. We hypothesized that patients with aplastic anemia (AA) may harbor mutations in GATA2. The coding regions and regulatory regions of GATA2 were sequenced in 99 patients with confirmed AA. Sequences from 100 normal individuals as well as published human genomes from unaffected individuals (dbSNP build 135 and 1000 Genomes Project) were used as controls. Genetic variants were confirmed in hematopoietic and somatic tissues. We identified 4 heterozygous mutations in regulatory regions of GATA2 in 5 patients. In two patients, a mutation at nucleotide 59T>G in exon 1 of isoform 2 was identified; both had severe AA in early adulthood refractory to immunosuppressive therapy. We noted this 59T>G mutation in two unrelated individuals with severe disseminated mycobacterial disease. We identified a mutation at nucleotide 20G>A in exon 2 of isoform 1, in a 3 year-old male with hepatitis-associated severe AA whose disease was refractory to multiple rounds of immunosuppressive therapy. Another mutation was present in 38G>A in exon 2 of isoform 1 in a 32 year old male with moderate AA and paroxysmal nocturnal hemoglobinuria (PNH). We also identified the exon 2 38G>A mutation in a patient with disseminated mycobacterial disease where reduced transcription of the mutant 38G>A allele was noted on RT-PCR. Finally, an intron 5, c.512+573 G>A variant was identified in an 18 year old male with severe AA who progressed after immunosuppressive therapy to MDS/AML. This variant, which causes a disruption of the FLI1 binding site, has also been found to be pathogenic in monoMAC syndrome. In summary, a subset of patients with AA were found to have mutations in GATA2 suggesting a role for the gene in the pathogenesis of bone marrow failure. It also may identify patients at higher risk of infectious complications, those who may have less advantageous responses to immune suppression, and command earlier bone marrow transplantation. Disclosures: No relevant conflicts of interest to declare.

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Hickstein, Dennis D., Nirali N. Shah, Alexandra F. Freeman, Christa Zerbe, Steven M. Holland, and Mark Parta. "Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Deficiency." Blood 126, no. 23 (December 3, 2015): 1214. http://dx.doi.org/10.1182/blood.v126.23.1214.1214.

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Abstract Background: Mutations in the zinc finger transcription factor GATA2 are responsible for: MonoMAC, monocytopenia with nontuberculous mycobacterial (NTM) infections; DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger's syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). Allogeneic hematopoietic stem cell transplant (HSCT) represents the only definitive therapy for GATA2 deficiency. Methods: Eleven patients with GATA2 deficiency received a myeloablative-conditioning regimen (2 matched related donors or MRD, 4 matched unrelated donors or URD, and 5 haploidentical related donors. MRD and URD received busulfan 3.2 mg/kg/day and fludarabine 40 mg/m2/day on days -6, -5, -4, and -3. Haploidentical related donors received cyclophosphamide 14.5 mg/kg on day's -6 and -5, fludarabine 30 mg/m2/day on day's -6 to -2, busulfan 3.2 mg/kg/day on day's -4 and -3, and 200 cGy TBI on day -1. MRD and URD recipients received tacrolimus and short course methotrexate post-transplant, while haploidentical related donor recipients received cyclophosphamide 50 mg/kg/day on days + 3 and +4 followed by tacrolimus and mycophenolate mofetil as post-transplant immunosuppression for graft-versus-host disease. Results: Ten of the 11 (91%) of patients are alive and disease-free at a mean follow-up of 12 months (range 1 mo to 24 mo). One URD recipient died from persistent acute myelogenous leukemia. Four patients developed graft-versus-host disease, one case Grade 4. All 10 patients who survived had complete reconstitution of the monocyte, NK, and B-lymphocyte compartments, the three cell compartments that were severely deficient pre-transplant. All 10 patients had reversal of the infection susceptibility phenotype. In particular, there were no recurrences of NTM infections. Importantly, all 10 patients had correction of the cytogenetic abnormalities present pre-transplant (5 patients with trisomy 8 and 1 patient with monosomy 7). Conclusions: Myeloablative HSCT in GATA2 deficiency results in uniform engraftment and reversal of the hematologic, cytogenetic, and clinical manifestations of GATA2 deficiency. There was a low regimen-related toxicity, even in this cohort of patients with considerable co-morbidities. We anticipate that with HSCT earlier in the clinical course, before significant organ damage or clonal evolution of MDS to AML or CMML occurs, the outcome of allogeneic HSCT in patients with GATA2 deficiency will continue to improve. Haploidentical related donor transplant appears to be particularly well suited for this disease, especially when the disease presents as a hypocellular myelodysplastic syndrome. Disclosures No relevant conflicts of interest to declare.

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Hickstein, Dennis D., Nirali N. Shah, Alexandra Freeman, Christa Zerbe, and Steven M. Holland. "Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Deficiency." Blood 128, no. 22 (December 2, 2016): 1500. http://dx.doi.org/10.1182/blood.v128.22.1500.1500.

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Abstract Background:Mutations in the zinc finger transcription factor GATA2 are responsible for: MonoMAC, monocytopenia with atypical mycobacterial infection (MAC); DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). Allogeneic hematopoietic stem cell transplant (HSCT) represents the only definitive therapy for GATA2 deficiency. Methods: We carried out myeloablative allogeneic hematopoietic stem cell transplant (HSCT) on 24 patients (mean age 24.9 years; range 16 to 46 years) with mutations in GATA2, or the MonoMAC syndrome, during the preceding three years. Three matched related donor (MRD) recipients and 13 matched unrelated donor (URD) recipients received busulfan 3.2 mg/kg/day and fludarabine 40 mg/m2/day on day's -6, -5, -4, and -3. Eight haploidentical related donor recipients received cyclophosphamide 14.5 mg/kg on day's -6 and -5, fludarabine 30 mg/m2/day on day's -6 to -2, busulfan 3.2 mg/kg/day on day's -4 and -3, and 200 cGy TBI on day -1. The majority of the MRD and URD recipients (n=13) received tacrolimus and short course methotrexate post-transplant as graft-versus host disease (GVHD) prophylaxis; three URD, while three received post-transplant cyclophosphamide (PT/CY) on days + 3 and +4 followed by tacrolimus and mycophenolate mofetil as post-transplant immunosuppression for GVHD. All 8 haploidentical related donor recipients received PT/CY as described followed by tacrolimus/methotrexate. Results:Twenty-two of the 24 patients are alive and disease-free at a mean follow-up of 13 months (range, 2 to 36 months). One matched URD recipient died from persistent AML 110 days post-transplant, and one matched URD recipient died from GVHD 2 years post-transplant. Despite a previous history of MAC in 11 patients, including 3 patients with active MAC at the time of HSCT, there were no recurrences of MAC during or following HSCT. Similarly, 13 patients had MDS with cytogenetic abnormalities at the time of HSCT (trisomy 8, monosomy 7, 5q-, trisomy 1q), and all 13 had resolution of their cytogenetic abnormalities with no late relapses following HSCT. Three patients had lymphedema at the time of HSCT (Emberger syndrome), which was not reversed. Twenty-three of the 24 patients had complete reconstitution of the monocyte, NK, and B-lymphocyte compartments, which were severely deficient pre-transplant. One URD who received PT/CT had poor graft reconstitution and required a CD34+ donor cell boost three months post-transplant. Four of the 13 MRD and URD recipients who received tacrolimus/methotrexate developed grade III-IV acute GVHD, and 3 of the 7 who were more than one-year post-HSCT developed moderate to severe chronic GVHD. No haploidentical related donor recipient developed grade III-IV GVHD or moderate to severe chronic GVHD. Conclusions: Myeloablative HSCT in GATA2 deficiency results in uniform engraftment and reversal of the hematologic, cytogenetic, and clinical manifestations of clinical manifestations of GATA2 deficiency with low regimen-related toxicity, even in this cohort of patients with considerable co-morbidities. We are currently using PT/CY in MRD and URD recipients with normal, favorable, or intermediate cytogenetics with isolated trisomy 8 to reduce the incidence of acute and chronic GVHD. We anticipate that with HSCT earlier in the clinical course, before significant organ damage or clonal evolution of MDS to AML occurs, the outcome of allogeneic HSCT in patients with GATA2 deficiency will continue to improve. Haploidentical related donor transplant appears to be particularly well suited for this disease, especially when the disease presents as a hypocellular MDS with or without trisomy 8. Disclosures No relevant conflicts of interest to declare.

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Zerbe, Christa S., Jennifer Cuellar-Rodriguez, Juan Gea-Banacloche, Steven M. Holland, and Dennis D. Hickstein. "Successful Haploidentical Hematopoietic Stem Cell Transplant for GATA2 Deficiency." Blood 124, no. 21 (December 6, 2014): 5838. http://dx.doi.org/10.1182/blood.v124.21.5838.5838.

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Abstract Background: GATA2 deficiency results in a clinical syndrome known variably as: MonoMAC for the lack of monocytes and atypical mycobacterial infections (MAC); DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger's syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). Reconstitution of the deficient cell compartments in GATA2 deficiency with allogeneic hematopoietic stem cell transplant (HSCT) results in reversal of the infection susceptibility and represents the only curative therapy for both the myeloid disease and the virally driven malignancies seen in this disorder. However, only about one-half of patients that require HSCT will have an HLA-matched related or unrelated donor. Moreover, the use of umbilical cord blood has been reported to be suboptimal in this cohort of patients in whom infection susceptibility underlies much of the need for a transplant. Methods: We performed haploidentical, related donor HSCT with high dose post-transplant cyclophosphamide (PT/CY) in 3 patients with GATA2 deficiency in whom a suitable HLA matched donor was not available. All three patients had a first degree relative (sibling) who shared at least 1 HLA-haplotype. The first patient, a 21 year-old Chinese woman presented with Hydroa Vacciniforme like T-cell lymphoma involving her lung, bowel (resulting in multiple small bowel resections and ileostomy), and skin (with large ulcerative lesions); multiple thrombotic cerebral events; and macrophage activation syndrome requiring etoposide and high dose prednisone in the intensive care unit (ICU). The second patient, a 20 year-old Hispanic female, presented with myelodysplasia (MDS), profound neutropenia, an invasive fungal sinusits due to Fusarium sp., and recurrent bacteremias. The third patient, a 45 year-old woman, presented with Emberger’s Syndrome, multiple episodes of bacterial and fungal sepsis and hypocellular MDS. All three patients received cyclophosphamide 14.5mg/kg on day’s -6 and-5; fludarabine 30mg/m2 on day’s -6 through -2; 200cGy of total body irradiation (TBI) on day -1. Patients 2 and 3 also received busulfan 3.2 mg/kg on day’s -4 and -3 because of MDS. All 3 patients received high dose PT/CY 50mg/kg on day’s +3 and +4, and mycophenolate mofetil and tacrolimus starting on day +5. Results: All 3 patients engrafted at a mean of 18 days and all are alive at a median follow-up of 9 months (range, 5 to 13 months). All three patients achieved 100% donor myeloid and lymphoid chimerim by day +100 post-transplant. The first patient had complete resolution of her T-cell lymphoma and macrophage activation syndrome, the second patient has had complete reversal of her hematopoietic and infectious phenotype, and the third patient has had resolution of her infectious complications that required continuous IV Daptomycin for 5 years prior to transplant. In addition, all three patients had complete reconstitution of the monocyte, NK cell, and B-lymphocyte compartments that were severely deficient prior to transplant. The main toxicity was mucositis, which required intravenous narcotics in all three patients. Lastly, the first patient developed late grade I liver graft-versus-host disease (GVHD) that was responsive to cyclosporine, the second patient developed grade I acute GVHD of skin that was responsive to topical steroids, and the third patient had no evidence of acute or chronic GVHD. Conclusions: Haploidentical, related donor HSCT represents a safe and effective viable alternative for patients with GATA2 deficiency who lack an HLA-matched donor, including patients such as our first patient who was in the ICU at the time of transplant. Disclosures No relevant conflicts of interest to declare.

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West, Robert R., Amy Hsu, Katherine R. Calvo, Jennifer Cuellar-Rodriguez, Steven M. Holland, and Dennis D. Hickstein. "ASXL1 mutations in GATA2-Deficiency Correlate with Leukemic Transformation." Blood 120, no. 21 (November 16, 2012): 405. http://dx.doi.org/10.1182/blood.v120.21.405.405.

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Abstract Abstract 405 Background: Recently, monoallelic mutations in the zinc-finger transcription factor GATA2 have been shown to be responsible for GATA2-deficiency, a syndrome characterized by opportunistic infections, frequently atypical mycobacterial infections or MAC, and a hypocellular myelodysplastic syndrome (MDS) that transforms into acute myelogenous leukemia (AML). GATA2-deficiency was previously known by several other names: MonoMAC (Monocytopenia and Atypical Mycobacterial Infection), DCML (Dendritic Cell Monocyte, Lymphoid Deficiency), Familial MDS/AML, or Emberger syndrome (lymphedema with monosomy 7). Heterogeneous genetic defects in GATA2 result in haploinsufficiency in both spontaneous and familial forms of the disease. Predicting the transformation from MDS to AML in GATA2-deficiency has clinical implications for both prognosis and the timing of hematopoietic stem cell transplantation. ASXL1, a gene related to the Drosophilia additional sex combs gene, encodes a chromatin binding/transcription repressor protein that is frequently mutated in MDS/AML. Mutations in ASXL1 are associated with reduced time to progression to AML and poor overall survival, independent of IPSS score. Methods: We sequenced the critical region of the ASXL1 gene in 20 patients with GATA2- deficiency to determine the frequency of ASXL1 mutations, and to correlate the presence of ASXL1 mutations with hematopoietic transformation. Since the ASXL1 mutations described in hematopoietic malignancies are located within the coding sequence of the two 3Õ-terminal exons (COSMIC: Catalogue of Somatic Mutations in Cancer), this ∼4.3kb region of ASLX1 was amplified by PCR and sequenced using five overlapping primer sets with substrate DNA isolated from mononuclear cell and granulocyte cell preparations from peripheral blood or bone marrow aspirates, or from extracts prepared from unfixed, unstained bone marrow aspirates. Mutations were confirmed with at least two independent PCR reactions with two unique primer sets. Results: Somatic ASXL1 mutations were detected in 8 of 20 patients with GATA2 mutations, 19/20 of whom had MDS. Five of these ASXL1 mutations have been previously associated with MDS/AML, including four independent cases of the most frequently described ASXL1 mutation (G646fs*12insG). The other four mutations were found once each; two of these were previously unreported (G652S(G>A) and L817fs*1delT). The patient cohort included two sisters with the same germline GATA2R398W mutation, but different somatic ASXL1 mutations (G464fs*12insG and R693X(C>T)). ASXL1 mutations were found in 4/5 GATA2- deficiency patients whose MDS had transformed into chronic myelomonocytic leukemia (CMML). Overall survival was lower for GATA2-deficiency patients with ASXL1 mutation (50% survival) compared to patients without ASXL1 mutation (83% survival), and was independent of IPSS score. Conclusions: ASXL1 is frequently mutated in patients with GATA2-deficiency with at least 40% of patients having a mutation in ASXL1 compared to a 10–15% mutation rate reported for all MDS/AML patients. ASXL1 mutation correlates with the development of CMML and with poor overall survival, as reported previously for MDS/AML patients. There was no correlation between the presence and type of ASXL1 mutation and the specific GATA2 mutation: the eight different ASXL1 mutation events were found in six different GATA2 mutant backgrounds. These results are directly relevant to the prognosis and the timing of hematopoietic stem cell transplantation for GATA2-deficiency. Disclosures: No relevant conflicts of interest to declare.

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Alter, Blanche P., Neelam Giri, Katherine R. Calvo, Irina Maric, Diane C. Arthur, Dennis D. Hickstein, Caroline A. Hastings, Michelle A. Lee, Amy Hsu, and Steven M. Holland. "Clinically Silent Carriers in Families with Myelodysplastic Syndrome Due to GATA2 Mutations." Blood 120, no. 21 (November 16, 2012): 1264. http://dx.doi.org/10.1182/blood.v120.21.1264.1264.

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Abstract Abstract 1264 Patients with familial myelodysplastic syndrome (MDS) associated with mutations in GATA2 are at increased risk of MDS and acute myeloid leukemia (AML). Specific clinical syndromes recently found to be due to mutations in GATA2 include MonoMAC (monocytopenia and mycobacterial infection), Emberger (MDS with severe lymphedema), and DCML (defects in dendritic cells, monocytes, and B and NK lymphoid cells). Features shared by many patients with these GATA2-associated syndromes include monocytopenia, markedly decreased B and NK cells, and clinical immunodeficiency manifested as warts and mycobacteria and fungal infections. MDS and/or AML occur with multilineage dyspoieses, particularly prominent in the megakaryocyte lineage (micromegakaryocytes, small mononuclear megakaryocytes, and large megakaryocytes with multiple separated nuclei). Several reports mention family members who are “asymptomatic,” without further details. We identified mutations in GATA2 in two of three families with familial MDS. In both families, one apparently healthy parent was found to have a GATA2 mutation; only in-depth laboratory examinations uncovered subtle findings consistent with familial GATA2 mutation in these clinically silent carriers. Family 1: The proband presented at age 15 with pancytopenia, and was found to have MDS and monosomy 7; he died from post-BMT complications including aspergillosis. His brother was found to have leukopenia, neutropenia and macrocytosis at age 13 during an infection with H1N1 influenza; the leukopenia and macrocytosis persisted. Six months later, repeat bone marrow showed early refractory anemia; the next year his marrow had myeloid dyspoiesis and dysplastic megakaryocytes; FISH showed −7 in 2.3% of cells, leading to classification as MDS-RCC. In retrospect, both boys had absolute monocytopenia (<100/uL). GATA2 sequencing of samples from the surviving brother and his 51 y.o. mother identified a deleterious mutation (c.1116_1130del15, p.C373del5). The mother had breast cancer at age 50, but otherwise was asymptomatic. Closer clinical examination revealed lower limb lymphedema, while laboratory studies revealed lymphopenia (360/uL), monocytopenia (110/uL), low lymphocyte subsets, especially CD19 (3/uL) and MCV = 100fL. Her marrow did not show overt dyspoiesis in myeloid or erythroid lineages; among mostly normal megakaryocytes there were occasional atypical forms, including some with hypolobulated or separated lobes; G-banded karyotyping and interphase FISH for −7/7q- were normal. She would not have been suspected to have GATA2-related MDS based on her clinical status, and is thus a silent carrier. Family 2: Three children in this family were diagnosed with MDS. The oldest had a history of warts and pancytopenia at age 18; his marrow showed MDS with trisomy 8. His brother was a compatible transplant donor, but he had mild pancytopenia and monocytopenia; his marrow had MDS and trisomy 8. Their sister was diagnosed at age 14 with MDS and trisomy 8; she, too, had monocytopenia. All 3 were transplanted. Subsequently, a mutation - c.1187G>A, p.R396Q - was found in GATA2, in all 3 brothers and their healthy father. He had normal blood counts (monocytes 500/uL) and immunoglobulins, but low B-cells in peripheral blood (CD20 23/uL) and bone marrow. His normocellular marrow had occasional atypical megakaryocytes with separated lobes, hypolobulation, and mononuclear and micromegakaryocytes. He, too, would not have been suspected to have GATA2-related MDS, and is also a clinically silent carrier. These two families indicate that familial GATA2-related MDS is a dominantly-inherited syndrome. In our two families, dominant inheritance was not initially considered, in part because the genetically affected parent was clinically asymptomatic. It is unclear whether GATA2 MDS shows “anticipation,” in which the younger generation is more severely affected than the parental generation. It is important that GATA2 be evaluated in families with apparently inherited childhood MDS, since the variable expression might lead inadvertently to selecting an asymptomatic GATA2 mutation carrier as a stem cell transplant donor. Genetic counseling needs to be provided with regard to risk to other family members. In addition, only long-term follow-up and surveillance of the clinically silent carriers will determine whether they remain unaffected. Disclosures: No relevant conflicts of interest to declare.

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Cuellar-Rodriguez, Jennifer, Juan Gea-Banacloche, Amy P. Hsu, Christa Zerbe, Alexandra Freeman, Kenneth N. Olivier, Katherine R. Calvo, Terry J. Fry, Steven M. Holland, and Dennis D. Hickstein. "Allogeneic Hematopoietic Stem Cell Transplant Reverses the Phenotype of GATA2 Deficiency." Blood 120, no. 21 (November 16, 2012): 3091. http://dx.doi.org/10.1182/blood.v120.21.3091.3091.

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Abstract Abstract 3091 Background: Recently, sporadic and heritable mutations in the zinc finger transcription factor GATA2 were shown to be responsible for four different syndromes in young adults coupling opportunistic infection with a predilection to develop myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). These four syndromes are: MonoMAC, monocytopenia with nontuberculous mycobacterial (NTM) infections; DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger's syndrome, lymphedema and MDS with monosomy 7; and familial MDS/AML. Life-threatening infections, and the transformation to AML, either alone or together, constitute a rationale for allogeneic hematopoietic stem cell transplant (HSCT) for GATA2 deficiency. Methods: We evaluated matched related, unrelated, and umbilical cord blood as donor sources for nonmyeloablative conditioning for HSCT in GATA2 deficiency. Twelve patients with GATA2 deficiency underwent allogeneic transplant: 4 received peripheral blood stem cells (PBSCs) from matched related-donors (MRD), 4 received PBSC from matched unrelated-donors (MUD), and 4 received umbilical cord blood (UCB) units. Recipients of MRD and MUD transplant received fludarabine and 200cGy of total body irradiation (TBI), while UCB recipients received cyclophosphamide 50 mg/kg, fludarabine, and 200cGy of TBI. All patients received tacrolimus and sirolimus for GVHD prophylaxis. This cohort of patients had considerable pre-transplant morbidity: two patients required baseline oxygen for pulmonary alveolar proteinosis, one of whom was on a ventilator at the time of transplant; one patient had active hepatitis C that was not responding to therapy; one patient had RAEB-2; two patients were platelet transfusion-dependent; one patient had recurrent strokes and culture negative endocarditis two months before transplant. Results: Median follow-up for patients was 14.4 months (range 0.2–38.2 months). Ten of 11 patients engrafted at a median of 10 days (range 0–76); engraftment was not evaluable in a recipient of an UCB transplant due to death early in the post-transplant period. One rejection occurred in a recipient of a double UCB transplant who had been heavily transfused pre-transplant. All patients who engrafted had complete reconstitution of the monocyte, NK, and B-lymphocyte compartments, the three cell compartments that were severely deficient pre-transplant, and all had reversal of the infection susceptibility phenotype, characteristic of the disease. In particular, there were no recurrences of NTM infection and extensive human papilloma virus infections regressed starting around 6 months post transplant. Two patients required a single cycle of pre-transplant chemotherapy for RAEB-1 and RAEB-2, respectively. In both patients the monosomy 6 and monosomy 7 clones have not recurred, now 2.5 years and 9 months following single UCB and MUD transplant, respectively. Three patients died, two early after transplant. One recipient of UCB, who had pre-transplant hepatitis C, died on day+7 of fulminant liver failure and sepsis. A second patient, who was intubated at the time of transplant because of severe pulmonary alveolar proteinosis and pulmonary hypertension, died on day + 88 of grade IV GVHD after MRD transplant. The third patient died 9 months after transplant of sepsis. One recipient of a MRD relapsed from her MDS at 1 year following transplant and was retransplanted using a myeloablative conditioning regimen. She is alive with no evidence of MDS at 3 months. Acute GVHD developed in 6 patients, five of which were steroid-responsive. One patient developed chronic GVHD. Other complications included immune mediated cytopenias that responded to rituximab and eltrombopag. Conclusions: Nonmyeloablative HSCT in GATA2 deficiency results in reconstitution of the severely deficient monocyte, B and NK cell populations and reversal of the infection susceptibility phenotype. The TRM in this cohort of patients with severe comorbidities was 25%. Now that genetic testing for GATA2 mutations is available, we anticipate that earlier diagnosis will enable patients to be transplanted earlier in the course of disease, before significant organ damage or clonal evolution of MDS to AML. Disclosures: No relevant conflicts of interest to declare.

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Cuellar-Rodriguez, Jennifer, Dennis D. Hickstein, Jennifer K. Grossman, Mark Parta, Juan Gea-Banacloche, Christa S. Zerbe, Alexandra F. Freeman, Steven M. Holland, and Katherine R. Calvo. "Nonmyeloablative Versus Myeloablative Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Deficiency." Blood 124, no. 21 (December 6, 2014): 1247. http://dx.doi.org/10.1182/blood.v124.21.1247.1247.

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Abstract Background: Mutations in the zinc finger transcription factor GATA2 are responsible for: MonoMAC, monocytopenia with nontuberculous mycobacterial (NTM) infections; DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger's syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). Allogeneic hematopoietic stem cell transplant (HSCT) is the only definitive therapy for GATA2 deficiency. Methods: We used matched related donors (MRD), matched unrelated donors (URD), umbilical cord blood (UCB), and haploidentical related donors in allogeneic HSCT for GATA2 deficiency. Fourteen patients received a nonmyeloablative conditioning regimen (4 MRD, 4 URD, 4 UCB, and 2 haplo donors). Five patients received a myeloablative conditioning regimen (1 MRD, 2 URD, and 2 haplo donors). In the nonmyeloablative group, MRD and MUD recipients received fludarabine and 200cGy of total body irradiation (TBI), UCB recipients received cyclophosphamide 50mg/kg, fludarabine 150 mg/m2, and 200cGy of TBI, and haploidentical related donor recipients received cyclophosphamide 29 mg/kg, fludarabine 150 mg/m2, and 200 cGy TBI. In the myeloablative group, MRD and URD received busulfan 12.8 mg/kg and fludarabine 160 mg/m2, and haploidentical related donors received the same regimen as in the nonmyeloablative regimen except for the addition of two days of busulfan 6.4 mg/kg total dose. Nonmyeloablative MRD and URD recipients received tacrolimus and sirolimus post-transplant, and myeloablative MRD and URD recipients received tacrolimus and short course methotrexate post-transplant. All haploidentical related donor recipients received cyclophosphamide 50 mg/kg/day on days + 3 and +4 followed by tacrolimus and mycophenolate mofetil. Three patients in the nonmyeloablative cohort required one or more rounds of pre-transplant chemotherapy because of an increased number of blasts, whereas none of the 5 patients in the myeloablative arm required pre-transplant chemotherapy. Results: In the nonmyeloablative cohort, 8 of 14 (57%) of patients are alive at a median follow-up of 3.7 years (range 12 months to 5 years). One MRD recipient died of GVHD and one relapsed, one URD recipient rejected the donor stem cells and died, three UCB recipient died (one rejection, one early death, and one donor cell leukemia), and one haploidentical recipient died from regimen-related toxicity. All 5 patients (100%) in the myeloablative group, including two recipients of haploidentical related donors, are alive at a median follow-up of 9.2 months (range 6 to 12 months). All patients who survived had complete reconstitution of the monocyte, NK, and B-lymphocyte compartments, the three cell compartments that were severely deficient pre-transplant, and all had reversal of the infection susceptibility phenotype, characteristic of the disease. In particular, there were no recurrences of non-tuberculous mycobacterial (NTM) infections. Conclusions: Nonmyeloablative HSCT results in reversal of the hematologic and clinical manifestations of GATA2 deficiency. However, a more intensive conditioning regimen with busulfan resulted in more uniform engraftment, a reduced risk of relapse, avoidance of pre-transplant chemotherapy, and a low regimen-related toxicity. We anticipate that with the use of a high-dose regimen with busulfan, the replacement of UCB with haploidentical related donors, and HSCT earlier in the clinical course, before significant organ damage or clonal evolution of MDS to AML or CMML, the outcome of allogeneic HSCT in patients with GATA2 deficiency will continue to improve. Disclosures No relevant conflicts of interest to declare.

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Cuellar-Rodriguez, Jennifer, Juan Gea-Banacloche, Christa Zerbe, Terry J. Fry, Kristin Baird, Steven M. Holland, and Dennis D. Hickstein. "Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplant For GATA2 Deficiency." Blood 122, no. 21 (November 15, 2013): 2113. http://dx.doi.org/10.1182/blood.v122.21.2113.2113.

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Abstract Background Heterozygous sporadic or inherited mutations in the GATA2 gene result in a syndrome known variably as: “MonoMAC” for monocytopenia with nontuberculous mycobacterial (NTM) infections; DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger's syndrome, lymphedema and MDS with monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). Life-threatening opportunistic infections and myeloid transformation constitute the rationale for allogeneic hematopoietic stem cell transplant (HSCT) for GATA2 deficiency. Methods We treated 14 patients with GATA2 deficiency using a nonmyeloablative-conditioning regimen and matched related donors (MRD) (n=4), matched unrelated donors (URD) (n=4), umbilical cord blood (UCB) (n=4), and haploidentical related donor (HD) (n=2) sources. There was considerable pre-transplant morbidity in this cohort of patients. MRD and URD recipients received 200 cGy of total body irradiation (TBI) and 3 days of fludarabine; UCB recipients received 200cGy TBI, cyclophosphamide 50 mg/kg on day -6, and 5 days of fludarabine; HD recipients received 200cGy TBI, cyclophosphamide 14.5 mg/kg on days -6 and -5, and fludarabine for 5 days. MRD, URD, and UCB recipients received tacrolimus and sirolimus for GVHD prophylaxis. HD recipients received cyclophosphamide 50 mg/kg on days + 3 and +4 followed by tacrolimus and mycophenolate mofetil. MRD and URD donor recipients received peripheral blood stem cells (PBSC) and HD donor recipients received bone marrow stem cells. Results (table 1): The median follow-up in the MRD cohort was 32 months, excluding one early death in a patient on a ventilator at the time of transplant. One patient relapsed one year post-transplant and required re-transplant using a myeloablative regimen. All 4 patients in this cohort developed acute GVHD. In the URD cohort, all patients are alive, however one patient rejected the PBSC graft and required a second URD transplant from a different donor. Two patients developed acute GVHD. In the UCB cohort, there was one early death from sepsis, one graft rejection, and one donor cell leukemia that occurred 2.5 years post-transplant. The remaining patient had a complicated course, but at 3 years post-transplant he is fully engrafted, on no medications, and has no GVHD. In the two patients who received HD transplants, one had progressed to proliferative CMML prior to transplant and died in the immediate post-transplant period. The second patient engrafted and is doing well two months post-transplant with resolution of an EBV-driven T cell lymphoma. All patients who engrafted had complete reconstitution of the monocyte, NK, and B lymphocyte compartments; all had correction of the underlying myeloid malignancy, and reversal of the infection susceptibility phenotype, characteristic of the disease. In particular, there were no recurrences of NTM. Conclusions Nonmyeloablative HSCT in GATA2 deficiency results in reconstitution of the severely deficient monocyte, B and NK cell populations and correction of the infection susceptibility phenotype. However, 1 of 4 MRD recipients developed a relapse of the original clone, and 1 of 4 URD recipients rejected the donor PBSC. The incidence of relapse and rejection, as well as the unfavorable cytogenetics in many patients, suggests that a more intense conditioning regimen is required to treat these patients. In this regard, we are now using a myeloablative regimen with busulfan and fludarabine. The poor outcome with UCB in this cohort of immunocompromised patients supports the use of HD transplants when a MRD or URD is not available. We anticipate that with increasing use of genetic testing for GATA2 mutations, patients will be transplanted earlier in the course of disease, before significant organ damage or clonal evolution of MDS to AML and CMML occurs, and that the outcome of allogeneic HSCT in these patients will continue to improve with these modifications in the transplant approach. Disclosures: No relevant conflicts of interest to declare.

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Hirabayashi, Shinsuke, Brigitte Strahm, Sandra Urbaniak, Axel Karow, Annamaria Cseh, Marry Van Den Heuvel, Selin Aytag, et al. "Unexpected High Frequency of GATA2 Mutations in Children with Non-Familial MDS and Monosomy 7." Blood 120, no. 21 (November 16, 2012): 1699. http://dx.doi.org/10.1182/blood.v120.21.1699.1699.

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Abstract Abstract 1699 Haploinsufficiency of GATA2 results in three overlapping clinical entities unified by the predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML): i) familial MDS/AML, ii) Emberger syndrome, and iii) an immunodeficiency termed monocytopenia with mycobacterium avium infections (MonoMAC)/ dendritic cell, monocyte, B- and NK-lymphoid deficiency (DCML). All these conditions manifest with a wide heterogeneity of symptoms predominantly affecting the hematologic and immune systems. To investigate the frequency of GATA2 defects in children and adolescents with MDS registered in the retrospective and prospective studies of the European Working Group of MDS and JMML in Childhood (EWOG-MDS), we first identified children from families with MDS/AML affecting multiple individuals, or children with MDS and preexisting lymphedema or immunodeficiency. We measured telomere length in hematopoietic cells to rule out an underlying defect of the telomerase complex, performed SNP-Array analysis, and excluded cases with germline RUNX1 aberrations. We identified heterozygous GATA2 mutations in 11 offspring of 8 distinct pedigrees: 4 previously reported missense mutations affecting the 2nd zinc finger (ZF2) T357A, S447R and R396Q/W; a novel exon 5 skipping mutation c.1018-10_1037del; and one novel nonsense mutation S201X and two novel frameshift mutations S139CfsX45, and V70LfsX114, all resulting in a premature stop codon prior to ZF2. The median age at diagnosis of MDS was 13.6 (11.0–16.9) years. Karyotype abnormalities were detected in 10/11 (91%) children: in 9 at initial presentation and in one during disease progression. Most patients carried the aneuploidies monosomy 7 (−7; n=5), trisomy 8 (+8; n=4), or both (n=1). Additionally, the recurrent translocation +1,der(1;7)(q10;p10) was detected in three patients. Interestingly, in one patient, the initial karyotype 45,XY,-7 transformed at relapse after hematopoietic stem cell transplantation (HSCT) to 46,XY,-7,+8,+21. Two additional patients with hypocellular MDS since adolescence and GATA2 hotspot mutations referred to us carried the aneuploidies −7 or +8, respectively. We next extended our study to children registered to EWOG-MDS in Germany with non-familial MDS and monosomy 7. Unexpectedly 8/51 (16%) patients with −7 carried GATA2 aberrations: 7 missense mutations within ZF2 and a germline 3.6Mb deletion 3q21.2–21.3 encompassing GATA2. In depth review of patient's history identified preexisting features of immunodeficiency as seen on laboratory tests and clinical exam (i.e. generalized verrucosis) in 5 of these 8 patients. The germline status was confirmed in cases where non-hematopoietic specimens were available. The combined analysis of all 21 patients identified additional comorbidities that, to our knowledge, were previously not reported in patients with GATA2-deficiency. These affected the urogenital system (nonselective glomerular proteinuria in one family, vesicoureteral reflux in a single case), neurodevelopmental delay and aggressive behavior in two cases, and ulcerative colitis in 2 families. At diagnosis of MDS, refractory cytopenia of childhood (RCC) was present in 43% of cases, while 33% presented with RAEB, and remaining 24% of patients with RAEBt and myelodysplasia related AML. Following HSCT as first line therapy, 10 of 12 children are alive, while all 4 children treated with AML-like therapy prior to HSCT succumbed. Five patients with RCC are followed closely with a watch and wait regimen. Finally, to study the genetic factors initiating clonal evolution, we subjected selected cases to targeted next generation sequencing of 103 cancer-associated genes. Based on preliminary data, some GATA2-deficient patients carry acquired mutations of genes previously reported in malignant processes (such as ASXL1, RUNX1, TET2, and 14 more genes). In summary, we identified a high frequency of GATA2 mutations among children and adolescents cases with sporadic MDS with monosomy 7 in children and adolescents. Some of these patients had a mild preexisting immunodeficiency. Outcome following HSCT without prior intensive chemotherapy was similar to what can be expected in children with MDS without GATA2 mutations. The genotype-phenotype correlation and mechanisms of clonal evolution are not understood and warrant further studies. Disclosures: No relevant conflicts of interest to declare.

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Novakova, Michaela, Ales Janda, Marcin W. Wlodarski, Martina Sukova, Vit Campr, Marketa Kubricanova Zaliova, Eva Fronkova, et al. "Defect in B Cell Production Driven By GATA2 Mutation Results in Their Absolute Reduction and Mature Phenotype in Pediatric Patients." Blood 124, no. 21 (December 6, 2014): 2746. http://dx.doi.org/10.1182/blood.v124.21.2746.2746.

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Abstract Introduction Germline mutations in GATA2 were recently identified as causative for several overlapping syndromes: MonoMAC (monocytopenia, mycobacterial infections), DCML (dendritic cells, monocytes, B and NK cells deficiency), Emberger syndrome (lymphedema, sensorineural deafness, multiple warts) and familiar myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Of note, GATA2 mutations were also found in children and young adults with “primary” MDS. Aplastic anemia (AA) constitutes an important differential diagnosis to pediatric MDS, particularly in patients with normal cytogenetics. Because of heterogeneous phenotype of GATA2 mutated patients, defining a set of typical findings would help in their earlier identification and understanding the natural course of the disease. Therefore we aimed to analyze monocytes and lymphocyte subpopulations with the emphasis on B cell lineage by flow cytometry (FC) and polymerase chain reaction (PCR) in all pediatric patients with GATA2 mutation diagnosed in the Czech Republic. Patients and methods Eleven pediatric patients were found to harbor GATA2 mutations in the Czech Republic so far. Three mutations were intronic. There was a clear male predominance (9/11). In 7 patients the disease manifested with MDS in childhood, 2 female patients were followed for immunodeficiency and developed MDS in adulthood. One another patient was diagnosed with interstitial lung disease and chronic EBV infection. His brother, carrying the same mutation, has mild neutropenia. Bone marrow (BM) and peripheral blood (PB) samples were analyzed by FC. The level of intronRSS-Kde recombination excision circles (KREC) and T-cell receptor excision circles (TREC) for assessment of proliferation history of B and T cells was examined by PCR. The control group comprised 26 GATA2 wild-type MDS (“other MDS”) patients and 36 AA patients. Results Disturbance of B cell compartment was the most frequently observed anomaly in the patients with GATA2 mutation. We observed a decrease of absolute and relative B cell numbers in PB and BM (n=9/11). In BM there was a decrease of immature CD10pos B cells (n=10) with proportional increase of plasma cells. Peripheral blood B cell immunophenotype was shifted towards memory B cells (n=5/7). Presence of normal B cell precursors CD19pos10pos34pos in BM was observed only in 1 patient in part of follow-up samples. Atypical malignant B lymphoblasts were present in another patient, whose MDS quickly progressed to AML with a clear switch to B lymphoid phenotype. Despite significantly reduced number of B cells the levels of IgG were normal in majority of patients. Only 2 patients had IgG hypogammaglobuliemia, in one patient with chronic active EBV infection IgG hypergammaglobulinemia was present. Slightly decreased IgA level was present in 6 patients. Although B cell numbers in other MDS control patients were significantly lower compared to AA, still the decrease was less prominent in comparison with GATA2. The decrease of immature and naive B cells in patients with GATA2 mutation was reflected in very low level of KREC in PB and BM. Stored newborn dry blood spots from 4 patients were evaluated for TREC and KREC numbers. Strikingly, only one patient had negative KREC levels (the youngest patient from our cohort with MDS diagnosed at age 4). The remaining 3 patients had normal TREC and KREC levels at birth. Thus, the deterioration of de novo production of B cells occurred supposedly postnatally in most patients. Low KREC levels were also present in some patients with other MDS (n=5). Relative monocytopenia was found in 2 patients, low NK cells were present in 6 patients. T cells were mostly of naive non-activated phenotype. Conclusions Changes in B cell compartment are the most characteristic feature in patients with GATA2 mutation. Decreased number of B cells together with a shift towards mature phenotype and decreased level of KREC reflect history of substantial B cell proliferation in an environment of impaired production. This process appears to happen postnatally and resemble normal ageing process, which is accelerated due to progenitor cell impairment. Immunophenotyping is a useful tool in identifying patients for GATA2 sequencing. Supported by GAUK 802214, IGA NT/14534-3, NT/13462-4, UNCE 204012, GAČR P301/10/1877 Disclosures No relevant conflicts of interest to declare.

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McReynolds, Lisa J., Peter D. Aplan, Donald Small, Li Ding, Kirby D. Johnson, Emery H. Bresnick, and Steven M. Holland. "Mouse Modeling of GATA2 Related MDS/AML." Blood 126, no. 23 (December 3, 2015): 2855. http://dx.doi.org/10.1182/blood.v126.23.2855.2855.

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Abstract GATA2 is a zinc finger transcription factor essential for embryonic and definitive hematopoiesis as well as lymphatic angiogenesis. Human GATA2 deficiency disease is caused by a variety of mutations in GATA2 which lead to the clinical phenotypes variously known as monocytopenia and mycobacterial disease (MonoMac), familial MDS/AML, dendritic cell, myeloid and NK cell lymphopenia (DCML), Emberger syndrome, and classical NK cell deficiency. Patients with GATA2 deficiency have an immunodeficiency with monocytopenia, NK, and B cell leukopenia; are susceptible to mycobacterial, viral and fungal infections as well as MDS and progression to AML. Additionally, patients may suffer from lymphedema and pulmonary alveolar proteinosis. GATA2 mutations have also been associated with aplastic anemia and severe congenital neutropenia. In order to understand the mechanisms underlying the development of MDS/AML in GATA2 deficiency we developed and analyzed a unique mouse model. The previously characterized Gata2+9.5+/- mouse has an intronic regulatory region mutation identical to one found in some patients. However, these mice do not develop MDS/AML spontaneously. We hypothesized that crossing these mice to other MDS/AML prone strains would accelerate the progression of MDS/AML. Specific HOX genes are implicated in this disease process. GATA2-deficient patients often develop monosomy 7 and ASXL1 mutations, both of which lead to the overexpression of HOX genes including HOXA9. The known AML translocation t(2;11)(q31;p15) results in the fusion of NUP98 and HOXD13 (NHD13) and the upregulation of HOX gene expression. Gata2 was identified in a mouse retroviral insertion screen as a potential collaborator in NHD13-mediated leukemogenesis. We hypothesized that hematopoietic specific Hox gene overexpression in a mouse with germline Gata2 haploinsufficiency would lead to the development of MDS/AML. This was done using the established NHD13 transgenic strain crossed to the Gata2+9.5+/- strain. The NHD13 mice express the fusion protein under the control of the hematopoietic specific vav promoter, and have up-regulation of Hoxa5, Hoxa7, Hoxa9, and Hoxa10. Secondly, elevated Flt3 ligand levels have been detected in GATA2-deficient patients as they progress from normal bone marrow morphology to MDS/AML. To model the hyper-activation of the receptor Flt3 by Flt3 ligand, we used a model of constitutively active Flt3, the Flt3-ITD mouse. Gata2 +9.5+/- mice were bred to the NHD13 and the Flt3-ITD transgenic strains and compound heterozygotes were analyzed. Gata2+9.5+/-;NHD13 compound heterozygous mice were born normally and at Mendelian ratios. No significant differences in blood cell counts were noted in Gata2+9.5+/-;NHD13 compound heterozygotes until disease progression. These mice developed aggressive AML at 9-14 months of age, similar ages and rates as the NHD13 only mice. Whereas compound Gata2+9.5+/-;Flt3-ITD mice are also born in Mendelian ratios, starting at 10 weeks of age they developed B-cell lymphopenia, similar to that which is seen in human GATA2 deficiency patients displaying B-cell loss early in disease. The Gata 2+9.5+/-; Flt3-ITD mice exhibited increased circulating c-Kit-positive cells in the peripheral blood. Studies to further characterize hematopoiesis in the Gata2+9.5+/-; Flt3-ITD mice, and analyze for the development of MDS/AML are in progress. The Gata 2+9.5+/-; Flt3-ITD mouse model holds promise for the further study of MDS/AML in the context of GATA2 haploinsufficiency. Disclosures Aplan: NIH Office of Technology Transfer: Patents & Royalties.

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Damian, Louise, Gaëtan Sauvêtre, Florent Marguet, Mikael Verdalle-Cazes, Maxime Battistella, and David Boutboul. "Pseudo-Sarcoidosis Revealing MonoMAC Syndrome." Journal of Clinical Immunology 38, no. 7 (October 2018): 739–41. http://dx.doi.org/10.1007/s10875-018-0551-6.

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18

Schnack, Jason, Aarti Mittal, and Ching-Fei Chang. "The New Great Pretender: Diagnosing the MonoMAC Syndrome." Chest 145, no. 3 (March 2014): 124A. http://dx.doi.org/10.1378/chest.1825052.

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19

Eguchi, Katsuhide, Masataka Ishimura, Motoshi Sonoda, Hiroaki Ono, Akira Shiraishi, Shunsuke Kanno, Yuhki Koga, Hidetoshi Takada, and Shouichi Ohga. "Nontuberculous mycobacteria-associated hemophagocytic lymphohistiocytosis in MonoMAC syndrome." Pediatric Blood & Cancer 65, no. 7 (March 1, 2018): e27017. http://dx.doi.org/10.1002/pbc.27017.

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Damian, L., Y. Benhamou, N. Girszyn, H. Lévesque, and G. Sauvetre. "Myosite granulomateuse inflammatoire et monocytopénie révélant un syndrome MonoMAC." La Revue de Médecine Interne 37 (December 2016): A190. http://dx.doi.org/10.1016/j.revmed.2016.10.234.

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Johnson, Jennifer A., Steven S. Yu, Michael Elist, Daniel Arkfeld, and Richard S. Panush. "Rheumatologic manifestations of the “MonoMAC” syndrome. a systematic review." Clinical Rheumatology 34, no. 9 (March 5, 2015): 1643–45. http://dx.doi.org/10.1007/s10067-015-2905-2.

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Ding, L.-W., T. Ikezoe, K.-T. Tan, M. Mori, A. Mayakonda, W. Chien, D.-C. Lin, et al. "Mutational profiling of a MonoMAC syndrome family with GATA2 deficiency." Leukemia 31, no. 1 (September 29, 2016): 244–45. http://dx.doi.org/10.1038/leu.2016.256.

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Raziq, Fazal I., Ahmed Abubaker, Eric Smith, and Mohammed Uddin. "Secondary pulmonary alveolar proteinosis in GATA-2 deficiency (MonoMAC syndrome)." BMJ Case Reports 13, no. 11 (November 2020): e238290. http://dx.doi.org/10.1136/bcr-2020-238290.

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We present here a case of a 29-year-old woman with a medical history of GATA-2 deficiency, who was under treatment for Mycobacterium avium intracellulare pneumonia. She presented with worsening dyspnoea with cough and fever. It was initially thought she had pneumonia but she was later diagnosed with Pulmonary Alveolar Proteinosis (PAP).

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Koegel, Ashley K., Inga Hofmann, Kristin Moffitt, Barbara Degar, Christine Duncan, and Venée N. Tubman. "Acute lymphoblastic leukemia in a patient with MonoMAC syndrome/GATA2haploinsufficiency." Pediatric Blood & Cancer 63, no. 10 (May 27, 2016): 1844–47. http://dx.doi.org/10.1002/pbc.26084.

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Raziq, Fazal, and Muhammad Usama. "PULMONARY ALVEOLAR PROTEINOSIS IN MYELODYSPLASTIC SYNDROME SECONDARY TO GATA-2 MUTATION (MONOMAC SYNDROME)." Chest 158, no. 4 (October 2020): A455. http://dx.doi.org/10.1016/j.chest.2020.08.439.

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Koegel, Ashley, Venee N. Tubman, and Inga Hofmann. "Acute Lymphoblastic Leukemia in a Patient with Monomac Syndrome/GATA2 Haploinsufficiency." Blood 126, no. 23 (December 3, 2015): 3729. http://dx.doi.org/10.1182/blood.v126.23.3729.3729.

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Abstract Background: Heterozygous germline mutations in GATA2 have been described in three distinct conditions: 1) familial myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML), 2) Emberger syndrome which is characterized by lymphedema, warts and predisposition to MDS/AML, 3) MonoMac syndrome which is comprised of atypical nontuberculous mycobacterial infection, monocyte, and B and natural killer cell lymphoid deficiency. It is now recognized that these conditions represent a spectrum of hematopoietic, lymphatic and immune system disorders due to GATA2 haplosinsufficiency. MDS/AML due to GATA2 mutation shows a unique histopathology with characteristic dysplasia and is often associated with monosomy 7. Although many patients with GATA2 haploinsufficiency are initially asymptomatic the majority of patients will ultimately experience a significant complication such as severe infections due to immunodeficiency, pulmonary alveolar proteinosis (PAP), thrombotic events, bone marrow failure, MDS and progression to AML. Allogenic hematopoietic stem cell transplant (HSCT) is the only curative treatment for patients with GATA2 haploinsufficiency and those who develop MDS/AML. Here we report a unique patient who presented with with acute lymphoblastic leukemia (ALL) and was later found to have classical features of MonoMAC syndrome and GATA2 haploinsufficiency. Case Summary: A previously healthy 11 year-old girl presented with fever, cellulitis, and pancytopenia. Bone marrow biopsy and aspirate were diagnostic for B-precursor acute lymphoblastic leukemia (ALL) with associated monosomy 7 and the following karyotype: 45,XX,-7,del(9)(p13),del(10)(q24). She was treated on Dana Farber Cancer Institute (DFCI) Consortium ALL Protocol 05-001, achieving a morphological and cytogenetic remission. During induction, she developed necrotizing aspergillus pneumonia and molluscum contagiousum. Her planned course of therapy was abbreviated due to the development of restrictive lung disease associated with PAP and disseminated Mycobacterium kansasii infection. Serial off therapy bone marrow studies were obtained given poor count recovery and revealed significant morphologic dysplasia, most prominent in the megakaryocytes. These findings were reminiscent of those characteristically seen in patients with GATA2 haploinsufficiency. Her infectious complications, profound monocytopenia, PAP and bone marrow dysplasia raised concern for MonoMAC Syndrome. Sanger Sequencing of GATA2 revealed a point mutation in the regulatory enhancer region of intron 5 (c.1017+572C>T) confirming the diagnosis. More than 3 years following remission of ALL, she developed a bone marrow relapse with her initial clone. Given her diagnosis of GATA2 haploinsufficiency, HSCT was selected as consolidation therapy in second remission. She succumbed to complications of HSCT 4 months after transplantation. Conclusion: Patients with GATA2 haploinsufficiency show a heterogeneous clinical presentation and are at high risk for MDS/AML often associated with monosomy 7. The development of ALL in association with GATA2 haploinsufficiency has not been described in the literature. Hematologist and oncologists should be aware that ALL may be associated with GATA2 haploinsufficiency and should be attuned to the clinical, laboratory and histopathologic features of the MonoMAC syndrome that would prompt additional testing and potentially alter treatment regimens. As allogenic HSCT is the only definitive therapy for patients with GATA2 mutation, consideration of immediate HSCT following induction of remission should be considered in patients with ALL and GATA2 haploinsufficiency. Further, as patients with GATA2 mutations can be asymptomatic, it is imperative to screen family members for GATA2 mutations and offer genetic counselling prior to consideration as potential bone marrow donors. Disclosures No relevant conflicts of interest to declare.

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Hsu, Amy P., Kirby D. Johnson, E. Liana Falcone, Rajendran Sanalkumar, Lauren Sanchez, Dennis D. Hickstein, Jennifer Cuellar-Rodriguez, et al. "GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome." Blood 121, no. 19 (May 9, 2013): 3830–37. http://dx.doi.org/10.1182/blood-2012-08-452763.

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Key Points Mutations in a conserved intronic enhancer element lead to GATA2 haploinsufficiency. Mutations in GATA2, regardless of mutation type, lead to decreased GATA2 transcript levels and a common global transcriptional profile.

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Katsumura, Koichi Ricardo, Chenxi Yang, Jing Zhang, Lingjun Li, Kirby D. Johnson, and Emery H. Bresnick. "Mechanistic Deficits Of a Leukemogenic GATA-2 Mutant." Blood 122, no. 21 (November 15, 2013): 3668. http://dx.doi.org/10.1182/blood.v122.21.3668.3668.

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Abstract Recent studies have demonstrated a role for the master regulator of hematopoiesis GATA-2 in MonoMAC Syndrome, a human immunodeficiency disorder associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Though GATA2 coding region and cis-regulatory element mutations underlie MonoMAC syndrome, many questions remain unanswered regarding how GATA-2 is controlled physiologically and how it is dysregulated in pathological contexts. We dissected how a T354M mutation in the GATA-2 DNA binding zinc finger, which is frequently detected in MonoMAC syndrome and familial MDS/AML, alters GATA-2 activity. The T354M mutation reduced GATA-2 chromatin occupancy, induced GATA-2 hyperphosphorylation, and disrupted GATA-2 subnuclear localization. These molecular phenotypes also characterized an additional familial MDS/AML-associated GATA-2 mutant (Δ355T). T354M hyperphosphorylation and ectopic subnuclear localization were detected in hematopoietic and non-hematopoietic cell lines. We developed a new model system in mouse aortic endothelial (MAE) cells to quantitate GATA-2 activity to regulate endogenous target genes. T354M exhibited significantly reduced activity in this assay (GATA-2: 200-fold activation; T354M: 7.7-fold activation). Mass spectrometric analysis of the phosphorylation states of GATA-2 and T354M revealed that the T354M mutation enhanced phosphorylation at several GATA-2 residues. Analysis of single phosphorylation site mutants indicated that only mutation of S192 (S192A) abolished T354M-induced hyperphosphorylation. The S192A mutation attenuated phosphorylation of sites within wild-type GATA-2 and reduced transactivation activity (50% decrease, p < 0.01). A distinct 60 amino acid (aa) region within the GATA-2 N-terminus was required for T354M hyperphosphorylation and ectopic subnuclear localization. Deletion of this sequence decreased GATA-2 transactivation activity (60 aa deletion: 85% decrease, p < 0.01; 10 aa deletion: 45% decrease, p < 0.05). GATA-1 lacks an analogous subnuclear targeting sequence, and accordingly, a GATA-1(T263M) mutant, which corresponds to the GATA-2(T354M) mutant, localized normally and was not hyperphosphorylated. However, a GATA-1 chimera containing the GATA-2 subnuclear targeting sequence localized to ectopic subnuclear foci in a T263M-dependent manner. The GATA-2 N-terminus endowed GATA-1 with the capacity to induce GATA-2 target genes. By contrast, a GATA-2 chimera containing the GATA-1 N-terminus exhibited normal subnuclear localization. Thus, the leukemogenic T354M mutation utilizes the GATA-2-specific subnuclear targeting sequence to disrupt the normal subnuclear localization pattern, and this disruption is associated with S192-dependent hyperphosphorylation. In addition to its involvement in AML, GATA-2 interfaces with RAS signaling to promote the development of non-small cell lung cancer. We discovered that RAS signaling promotes S192-dependent GATA-2 hyperphosphorylation and ectopic subnuclear localization and propose that GATA-2 is an important component in oncogenic RAS-dependent leukemogenesis, which is being formally tested using innovative mouse models. In summary, dissecting the mechanistic deficits of a leukemogenic GATA-2 mutant revealed unexpected insights into mechanisms underlying physiological GATA-2 function and GATA-2-dependent hematologic pathologies. Disclosures: No relevant conflicts of interest to declare.

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Camargo, J. F., S. A. Lobo, A. P. Hsu, C. S. Zerbe, G. P. Wormser, and S. M. Holland. "MonoMAC Syndrome in a Patient With a GATA2 Mutation: Case Report and Review of the Literature." Clinical Infectious Diseases 57, no. 5 (May 31, 2013): 697–99. http://dx.doi.org/10.1093/cid/cit368.

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Spinner, Michael A., Camila Odio, Katherine R. Calvo, Amy P. Hsu, Christa S. Zerbe, Jennifer Cuellar-Rodriguez, Jennifer P. Ker, et al. "Hemophagocytic Lymphohistiocytosis Associated with NK Cell Dysfunction and Disseminated Herpesvirus Infection in GATA2 Deficiency/Monomac Syndrome." Blood 124, no. 21 (December 6, 2014): 4978. http://dx.doi.org/10.1182/blood.v124.21.4978.4978.

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Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of excessive immune activation. Herpesvirus infection is a common trigger of HLH, and in some patients may indicate an underlying immunodeficiency. Primary immunodeficiencies associated with HLH are often characterized by impaired cytotoxic function of NK cells and/or cytotoxic T lymphocytes and include Chediak-Higashi, Hermansky-Pudlak, and Griscelli syndromes and the X-linked lymphoproliferative disorders, SAP and XIAP deficiency. GATA2 deficiency, also known as MonoMAC syndrome, is a primary immunodeficiency resulting from haploinsufficiency of the GATA2 transcription factor, a master regulator of hematopoiesis. Clinically, GATA2 deficiency is characterized by progressive cytopenias of monocytes, dendritic cells, and B and NK lymphocytes; susceptibility to infection with human papillomavirus, herpesviruses, nontuberculous mycobacteria, and invasive fungi; and bone marrow failure with risk for clonal evolution to myelodysplastic syndrome and acute myelogenous leukemia. Additional manifestations may include pulmonary alveolar proteinosis, congenital lymphedema, and sensorineural hearing loss. We report two patients with GATA2 deficiency/MonoMAC syndrome who developed aggressive HLH in the setting of marked NK cell dysfunction and disseminated herpesvirus infection. Case 1 The patient was an African-American female with severe bilateral lymphedema since age 9 requiring multiple hospitalizations for lymphedema cellulitis. At age 12, she was hospitalized for severe pulmonary blastomycosis with necrotizing pneumonia. An immunologic workup revealed profound monocytopenia and B and NK lymphocytopenia, and NK functional testing revealed markedly reduced cytotoxicity and near absence of the CD56(bright) subset. Genetic testing for mutations in PRF1, UNC13D, and STX11 was negative. At age 18, she presented with septic shock and persistent fevers despite empiric antibiotics, and HSV-1 DNA was detected in the blood. The diagnosis of MonoMAC syndrome was strongly suspected in light of her congenital lymphedema and highly characteristic cytopenias and infections. Unfortunately, she rapidly decompensated and developed massive hyperferritinemia, hypofibrinogenemia, pancytopenia, and fulminant hepatitis concerning for HSV-1-driven HLH. An autopsy following her death revealed disseminated HSV-1 infection in the lungs, liver, and genitalia, and a hypocellular bone marrow with hemophagocytosis. The cause of death was HLH in the setting of NK cell deficiency and widespread HSV-1 infection. Genetic testing for GATA2 mutation was performed posthumously and is currently in progress. Case 2 A Chinese female presented at age 20 with persistent fevers, cervical lymphadenopathy, and cutaneous ulcers. Mycobacterium avium complex was identified in the sputum and urine, and she was treated with clarithromycin, rifampin, and ethambutol. HIV testing was negative. Biopsy of her skin lesions revealed an EBV+ hydroa vaccineforme-like cutaneous T-cell lymphoma, and she was found to have significant EBV viremia with over 1 million copies/mL detected by quantitative PCR. An immunologic workup revealed profound B and NK lymphocytopenia. Monoallelic GATA2 mRNA expression was demonstrated leading to haploinsufficiency. She developed persistent fevers, worsening hyperferritinemia, hypofibrinogenemia, pancytopenia, and transaminitis. Bone marrow biopsy revealed a hypocellular marrow with EBV+ T cells and abundant hemophagocytosis. She was diagnosed with EBV-driven HLH and was treated with etoposide and dexamethasone followed by nonmyeloablative, haploidentical related donor stem cell transplant. She is currently 12-months post-transplant with an undetectable EBV viral load and complete resolution of her T cell lymphoma and HLH. Conclusion GATA2 deficiency is associated with NK cell dysfunction and disseminated herpesvirus infection, which can lead to aggressive HLH. Genetic testing for GATA2 mutation should be considered in patients with HLH and underlying NK cell deficiency and/or herpesvirus infection. NK functional testing typically shows markedly reduced cytotoxicity and near absence of the CD56(bright) subset. Allogeneic transplant represents a potentially curative approach in this setting. Disclosures No relevant conflicts of interest to declare.

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Moraes-Fontes, Maria Francisca, Íris Caramalho, Amy P. Hsu, Steven M. Holland, and Manuel Abecasis. "MonoMAC Syndrome Caused by a Novel GATA2 Mutation Successfully Treated by Allogeneic Hematopoietic Stem Cell Transplantation." Journal of Clinical Immunology 39, no. 1 (November 26, 2018): 4–6. http://dx.doi.org/10.1007/s10875-018-0576-x.

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Johnson, Kirby D., Xin Gao, Rajendran Sanalkumar, Amy P. Hsu, Myung-Jeom Ryu, Jinyong Wang, Meghan E. Boyer, et al. "Genetic Determinants of the Definitive Hematopoietic Stem/Progenitor Cell Compartment." Blood 120, no. 21 (November 16, 2012): 1226. http://dx.doi.org/10.1182/blood.v120.21.1226.1226.

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Abstract Abstract 1226 How transcriptional and post-transcriptional mechanisms control the levels/activities of master developmental regulators has fundamental importance for understanding complex developmental processes such as hematopoiesis and associated pathological disorders. GATA-2 is an essential regulator of hematopoiesis, and GATA-2 mutations characterize heritable disease associated with myelodysplastic syndrome and acute myeloid leukemia, including MonoMAC (syndrome of monocytopendia, B and NK cell lymphopenia, and mycobacterial, fungal and viral infection). However, many questions remain unanswered regarding mechanisms underlying GATA-2 regulation and function. We demonstrated that a MonoMAC patient harbors a 28 bp deletion within GATA2 intron 5 that eliminates a conserved E-box and 5 base pairs of an 8 base pair spacer between the E-box and a conserved GATA motif, which constitutes an E-box-GATA composite element. This composite element resides within the +9.5 kb “GATA switch site” that binds GATA-2 and GATA-1 in the transcriptionally active and repressed states, respectively, and confers hematopoietic and vascular endothelial enhancer activities in transgenic mouse embryos. Importantly, this patient lacked mutations in the GATA2 coding sequence characteristic of other MonoMAC patients, but exhibited prototypical MonoMAC. To elucidate the mechanism underlying the function of the +9.5 composite element, we generated a targeted deletion of the murine element, which yielded embryonic lethality at E13 to E14. Prior to death, +9.5−/− mice exhibit reduced liver size, hemorrhaging, and edema. Nucleated primitive red cells are abundant in the +9.5−/− embryos, in contrast to Gata2 knockout mice, which die at approximately E10.5 from anemia due to failure of primitive and definitive hematopoiesis. Furthermore, primitive erythroid (EryP) colony assays conducted with yolk sacs revealed that the mutation does not affect primitive erythroid precursor functionality. However, the +9.5 deletion strongly reduced Gata2 expression at sites of definitive hematopoiesis, including the fetal liver (8.1 fold, P < 0.004) and cultured explants of the hematopoietic stem cell-generating Aortic Gonadal Mesonephric (AGM) region (4.0 fold, P < 0.001). The homozygous mutant animals exhibited a nearly complete loss of hematopoietic stem cells as determined by flow cytometry (20-fold reduction of Lin-Mac1+CD41-CD48-CD150+Sca+Kit+ cells, P < 0.005) and competitive repopulation (complete loss, P < 0.02) assays, as well as progenitors as determined by colony assays (BFU-E, 60-fold reduction, P < 0.002; CFU-GM, 8.8-fold reduction, P < 0.0001; CFU-GEMM, 19-fold reduction, P < 0.001). To investigate the underlying mechanisms, we developed an allele-specific Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE) assay with heterozygous fetal liver cells to test whether the deletion influences Gata2 chromatin accessibility at the +9.5 region. The deletion significantly reduced (8.4 fold reduction, P < 0.001) chromatin accessibility at this region within the mutant allele, while the wild type allele was unaffected. Thus, any potential remaining cis-elements are insufficient to confer chromatin accessibility, supporting a model in which the transcription factors that normally occupy this GATA switch site lose the capacity to access their respective cis-elements in the context of the mutant allele. Our human and murine studies have therefore revealed a cis-element indispensable for the regulation of Gata2 expression in multiple developmental contexts and necessary for the generation of the definitive hematopoietic stem/progenitor cell compartment. As additional elements are likely to confer Gata2 expression in distinct contexts, including primitive erythropoiesis, we have implemented a multi-faceted effort to identify such elements and to compare their mechanisms with that of the +9.5 site, which will provide fundamental insights into genetic mechanisms controlling normal and malignant hematopoiesis. Disclosures: No relevant conflicts of interest to declare.

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Cada, Michaela, Irene Lara-Corrales, Yigal Dror, Stephen Feanny, Vy Hong-Diep Kim, and Eyal Grunebaum. "Monocytosis in a patient with a novel GATA2 mutation." LymphoSign Journal 2, no. 2 (June 1, 2015): 85–90. http://dx.doi.org/10.14785/lpsn-2014-0022.

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GATA2-associated disorders include: (i) monocytopenia with mycobacterial infections (MonoMAC); (ii) dendritic cell, monocyte, B and NK lymphoid deficiency; (iii) familial myelodysplastic syndrome (MDS) and acute myeloid leukemia; and (iv) congenital deafness with lower limb lymphedema deficiency (Emberger syndrome). Markedly reduced or absent monocytes have been considered as the hallmark of the disease. Here we report on a patient that presented in infancy with hearing loss and lymphedema. By 4 years of age the patient developed acne, disseminated warts, lymphadenopathy, and MDS, yet with increased monocyte as well as normal NK- and B-cell numbers. The patient was found to have a novel mutation in GATA2 that was predicted to disrupt the C-terminal zinc finger. Importantly, and in contrast to common concepts, GATA2-associated syndromes might present with monocytosis. Statement of novelty: We describe a novel mutation in GATA2 associated with monocytosis.

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Hsu, Amy P., Elizabeth P. Sampaio, Javed Khan, Katherine R. Calvo, Jacob E. Lemieux, Smita Y. Patel, David M. Frucht, et al. "Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome." Blood 118, no. 10 (September 8, 2011): 2653–55. http://dx.doi.org/10.1182/blood-2011-05-356352.

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Abstract The syndrome of monocytopenia, B-cell and NK-cell lymphopenia, and mycobacterial, fungal, and viral infections is associated with myelodysplasia, cytogenetic abnormalities, pulmonary alveolar proteinosis, and myeloid leukemias. Both autosomal dominant and sporadic cases occur. We identified 12 distinct mutations in GATA2 affecting 20 patients and relatives with this syndrome, including recurrent missense mutations affecting the zinc finger-2 domain (R398W and T354M), suggesting dominant interference of gene function. Four discrete insertion/deletion mutations leading to frame shifts and premature termination implicate haploinsufficiency as a possible mechanism of action as well. These mutations were found in hematopoietic and somatic tissues, and several were identified in families, indicating germline transmission. Thus, GATA2 joins RUNX1 and CEBPA not only as a familial leukemia gene but also as a cause of a complex congenital immunodeficiency that evolves over decades and combines predisposition to infection and myeloid malignancy.

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Human, Andrea, Luis Murguia-Favela, Lee Benson, Idan Roifman, and Eyal Grunebaum. "Cardiovascular abnormalities in primary immunodeficiency diseases." LymphoSign Journal 2, no. 3 (September 2015): 107–34. http://dx.doi.org/10.14785/lpsn-2014-0013.

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In recent years, increasing numbers of patients with primary immune deficiency (PID) are being recognized as also suffering from cardiovascular system (CVS) abnormalities. These CVS defects might be explained by infectious or autoimmune etiologies, as well as by the role of specific genes and the immune system in the development and function of CVS tissues. Here, we provide the first comprehensive review of the clinical, potentially pathogenic mechanisms, and the management of PID, as well as the associated immune and CVS defects. In addition to some well-known associations of PID with CVS abnormalities, such as DiGeorge syndrome and CHARGE anomaly, we describe the cardiac defects associated with Omenn syndrome, calcium channel deficiencies, DNA repair defects, common variable immunodeficiency, Roifman syndrome, various neutrophil/macrophage defects, FADD deficiency, and HOIL1 deficiency. Moreover, we detail the vascular abnormalities recognized in chronic mucocutaneous candidiasis, chronic granulomatous disease, Wiskott–Aldrich syndrome, Schimke immuno-osseus dysplasia, hyper-IgE syndrome, MonoMAC syndrome, and X-linked lymphoproliferative disease. In conclusion, the expanding spectrum of PID requires increased alertness to the possibility of CVS involvement as an important contributor to the diagnosis and management of these patients.

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Stieglitz, Elliot, Y. Lucy Liu, Peter D. Emanuel, Robert P. Castleberry, Todd Michael Cooper, Kevin Shannon, and Mignon L. Loh. "Mutations In GATA2 Are Rare In Juvenile Myelomonocytic Leukemia." Blood 122, no. 21 (November 15, 2013): 1526. http://dx.doi.org/10.1182/blood.v122.21.1526.1526.

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Abstract Germline mutations in GATA2, a gene that encodes for transcription factors involved in hematopoiesis and vascular development, have recently been described in MonoMAC syndrome, Emberger syndrome and in select cases of mild chronic neutropenia. These disorders are unified by their predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Patients with MonoMAC syndrome have also been noted to display monosomy 7 in their bone marrows in up to 50% of cases. Overexpression of GATA2 due to somatic mutations in cases of de novo pediatric AML, has also been shown to be a negative predictor of outcome. Juvenile myelomonocytic leukemia is a rare childhood malignancy with overlapping features of MDS and myeloproliferative neoplasm (MPN) that can transform to AML and is characterized by hyperactive RAS signaling. Mutations in NF1, NRAS, KRAS, PTPN11, and CBL are found in 85-90% of newly diagnosed patients, and monosomy 7 is the most common recurrent karyotypic abnormality seen in JMML. We therefore hypothesized that mutations in GATA2 may play a role in the development of JMML. Samples from 57 patients with JMML were screened for GATA2 mutations. Patient samples and clinical data were collected from the Children's Oncology Group (COG) trial AAML0122. DNA was extracted as per previous protocols from peripheral blood or bone marrow and whole genome amplified using Qiagen REPLI-g kit according to manufacturer specifications. We performed bidirectional Sanger sequencing (Beckman Coulter Genomics) of the entire coding region of GATA2 (NM_001145661.1) and aligned the sequences using CLC Workbench software (CLC Bio, Aarhus, Denmark). Only missense, splice site or nonsense mutations were evaluated using SIFT (Sorting Tolerant From Intolerant) to predict the impact on the structure and function of identified mutations on the protein. Patient J384 was found to have a nonsense point mutation at c.988C>T (R330X) in the N-terminal region of the zinc finger portion of the protein (Figure 1a). This hotspot mutation has been reported in several patients with mild chronic neutropenia who displayed a predisposition to developing MDS and AML. The patient was also found to have a missense point mutation at c.962T>G (L321R) predicted to be damaging by SIFT. Subcloning of the gene using a TA cloning kit with pCR 2.1 vector (Invitrogen), followed by direct sequencing of individual colony picks, revealed that the two sequence variants only occurred in a trans configuration. Out of 40 amplicons sequenced, 20 were found to have the c.988C>T transition, 16 were found to be have the c.962T>G variant, and four were found to be wild type. We therefore hypothesize that the c.988C>T was inherited as a germline event and that c.962T>G was somatically acquired in the majority of the remaining wild type alleles. No other point mutations or insertions/deletions were discovered in this cohort.Figure 1Identification of 2 distinct GATA2 mutations in patient J384.Figure 1. Identification of 2 distinct GATA2 mutations in patient J384. This patient was previously identified to have a KRAS G12D mutation (c.35G>A) as well as monosomy 7. This patient died prior to undergoing transplant within months of diagnosis. While the patient technically met criteria for the diagnosis of JMML, it should be noted there were several atypical features, including older age at diagnosis (4 years and 10 months), and absence of hypersensitivity in myeloid progenitor cells to the cytokine granulocyte–macrophage colony stimulating factor (GM-CSF) in colony assay. This raises the possibility that patient J384 actually had MonoMAC syndrome with MDS and not JMML. This represents the first description of a GATA2 mutation in a patient suspected of having JMML. To our knowledge, this is the first report of a biallelic mutation in GATA2, combining a germline mutation with somatic acquisition. In addition, MonoMAC syndrome has not been reported to be associated with KRAS mutations to date. GATA2 mutations should therefore be considered in patients with atypical features of MDS or JMML. Panel (a) Bidirectional sequencing of patient sample J384 revealed two distinct sequence variants in both the forward (shown here) and reverse strands. Panel (b) Sequencing of 40 individual colony picks revealed that each sequence variant occurred in a trans configuration (CP 9 and CP13 are shown here as examples). In addition, 10% of colony picks (i.e. CP 32) revealed a wild type sequence, indicating that at least one of the two variants was a somatic event. Disclosures: No relevant conflicts of interest to declare.

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Bold, Tyler D., Matthew P. Cheng, Rahul S. Vedula, Francisco M. Marty, and R. Coleman Lindsley. "1140. GATA2 Mutations Are Frequently Identified Among Patients With Myeloid Malignancies Who Develop Invasive Aspergillosis." Open Forum Infectious Diseases 5, suppl_1 (November 2018): S342. http://dx.doi.org/10.1093/ofid/ofy210.973.

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Abstract Background Patients with myeloid malignancies are at risk of invasive aspergillosis (IA), a cause of significant morbidity and mortality. Identification of patients at higher risk for IA may help optimize prophylactic or preemptive treatment decisions. Molecular genetic testing used to risk-stratify and guide therapy for hematologic malignancies may also have applicability toward predicting infectious outcomes. The purpose of this study was to identify mutations that may increase risk for IA among patients with myeloid malignancies. Methods We identified patients cared for at Dana-Farber/Brigham and Women’s Cancer Center between March 1, 2015 and January 31, 2018 who were diagnosed with probable or proven IA during the treatment of myeloid malignancies including acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We reviewed pathogenic mutations detected by the Rapid Heme Panel (RHP), a clinical targeted next-generation sequencing panel of 95 recurrently mutated genes in hematologic malignancies. Results Twenty-four patients with myeloid malignancy (AML 20, MDS 4) were diagnosed with IA, 20 of whom (AML 17, MDS 3) had undergone genetic testing with the RHP at the time of their cancer diagnosis. We found that three of 20 patients (15%) had a pathogenic mutation in GATA2. All were missense mutations within the functional zinc-finger domains, including one resulting in an R398W amino acid change, one of the spectrum of germline mutations known to cause the primary immunodeficiency MonoMAC. Patients with GATA2 mutations in our cohort were ages 35–68 and variant allele fraction ranged from 16.3% to 49.7%, raising the possibility that both inherited and acquired GATA2 dysfunction could incur a similar infectious risk. Conclusion Mutations in GATA2, a gene associated with MonoMAC syndrome, were common among patients with myeloid malignancy who developed IA. These data suggest that personalized genetic analyses of patients with underlying hematologic malignancy may also be useful for assessment of infectious risk. Disclosures All authors: No reported disclosures.

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Hofmann, Inga, Daniel Kierstead, Jennie Krasker, Dean Campagna, Klaus Schmitz-Abe, Kyriacos Markianos, Michelle A. Lee, et al. "GATA2 Mutations In Pediatric Myelodysplastic Syndromes and Bone Marrow Failure." Blood 122, no. 21 (November 15, 2013): 1520. http://dx.doi.org/10.1182/blood.v122.21.1520.1520.

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Abstract Introduction Inherited bone marrow failure syndromes (IBMFS), idiopathic aplastic anemia (AA), and myelodysplastic syndromes (MDS) represent a spectrum of bone marrow failure (BMF) conditions for which the underlying genetics and pathophysiology is still poorly understood. Heterozygous germline mutations in GATA2 have recently been described in three distinct conditions that include familial MDS/AML, Emberger syndrome and MonoMac syndrome, each of which exhibits great clinical heterogeneity. The Pediatric MDS and BMF Registry was established in 2010 to carefully characterize clinical and histopathologic phenotypes and investigate the molecular basis for these disorders. To date 158 eligible patients/probands and 28 family members have been enrolled. The goal of this study was to determine the prevalence of GATA2 mutations in pediatric patients with MDS and BMF and characterize their clinical and histopathologic phenotypes. Materials and Methods Sanger sequencing of GATA2 was initially performed on 3 families with a history of familial MDS and 103 patients with sporadic appearing primary MDS, AA or an unclassified BMF enrolled in the Pediatric MDS and BMF Registry. Family members were assessed in patients with pathogenic mutation to determine if the disease was inherited or sporadic. Mutations were confirmed in somatic and germline tissue wherever possible. IBMFS were ruled out by molecular testing. Rigorous phenotype analysis included clinical and laboratory data, and standardized centralized pathology review. Whole exome sequencing (WES) was performed on a subset of patients to evaluate additional cooperating mutations and possible secondary somatic events and clonal evolution. Possible candidate genes were verified by Sanger sequencing. Results We identified pathogenic GATA2 mutations in a total of 16 individuals, including 12 patients (7 familial MDS cases and 5 sporadic MDS/BMF cases) and 4 first-degree relatives from 5 kindreds. Most mutations clustered in zinc finger 2. Previously identified mutations such as N371K and R396Q as well as novel point and frame shift mutations were identified. The median age at diagnosis was 15 years. There was strong male predominance (n=11). The clinico-pathologic diagnoses were RAEB/AML (n=4), refractory cytopenia of childhood (n=6) and MonoMac/other (n=6). Two out of the four families presented with features of Emberger syndrome. Two individuals presented with characteristic features of MonoMac Syndrome, of which one also showed bone marrow failure and pulmonary fibrosis suggestive of telomere disease. Very short telomeres (below the first percentile) were detected in all lymphocyte subsets consistent with dyskeratosis congenita (DC). However, genetic analysis did not reveal any of the known DC associated genes. Other associated pathology included severe gastrointestinal bleeding (n=2), severe polyneuropathy (n=2) and other cancers (n=1). A morphologically distinctive megakaryocytic dysplasia was a characteristic finding on histopathology. Monosomy 7 was the most common acquired cytogenetic abnormalities (n=6). Given this association we identified several additional individuals with MDS and monosomy 7 from our pathology archives and identified 2 additional patients with pathogenic GATA2 mutations. Secondary somatic mutations identified by WES included ASXL1. Thirteen out of the 14 pediatric patients with GATA2 mutations underwent hematopoietic stem cell transplant (HSCT). Ten out of these 13 patients are alive. Conclusion GATA2 mutations occur at a higher frequency than previously anticipated in pediatric MDS, and BMF, often occur sporadically and are associated with monosomy 7. While the clinical presentation is heterogeneous, the histopathologic features are often unique. Somatic genetic alterations likely play a role in clonal evolution. Given its significant implications for treatment decisions and donor selection GATA2 mutation screening should be performed on all patients with MDS, AA, and BMF disorders excluding classical IBMFS, and potential related donors. Disclosures: No relevant conflicts of interest to declare.

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39

Zughaier, Susu M., Henry C. Ryley, and Simon K. Jackson. "Lipopolysaccharide (LPS) from Burkholderia cepacia Is More Active than LPS from Pseudomonas aeruginosa and Stenotrophomonas maltophilia in Stimulating Tumor Necrosis Factor Alpha from Human Monocytes." Infection and Immunity 67, no. 3 (March 1, 1999): 1505–7. http://dx.doi.org/10.1128/iai.67.3.1505-1507.1999.

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ABSTRACT Whole cells and lipopolysaccharides (LPSs) extracted fromBurkholderia cepacia, Pseudomonas aeruginosa,Stenotrophomonas maltophilia, and Escherichia coli were compared in their ability to stimulate tumor necrosis factor alpha (TNF-α) from the human monocyte cell line MonoMac-6.B. cepacia LPS, on a weight-for-weight basis, was found to have TNF-α-inducing activity similar to that of LPS from E. coli, which was approximately four- and eightfold greater than the activity of LPSs from P. aeruginosa and S. maltophilia, respectively. The LPS-stimulated TNF-α production from monocytes was found to be CD14 dependent. These results suggest that B. cepacia LPS might play a role in the pathogenesis of inflammatory lung disease in cystic fibrosis, and in some patients it might be responsible, at least in part, for the sepsis-like cepacia syndrome.

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40

Seidel, Markus G. "Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment." Blood 124, no. 15 (October 9, 2014): 2337–44. http://dx.doi.org/10.1182/blood-2014-06-583260.

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Abstract Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches.

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Pasquet, Marlène, Christine Bellanné-Chantelot, Suzanne Tavitian, Naïs Prade, Blandine Beaupain, Olivier LaRochelle, Arnaud Petit, et al. "High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia." Blood 121, no. 5 (January 31, 2013): 822–29. http://dx.doi.org/10.1182/blood-2012-08-447367.

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42

Shen, Yingying, Yuzhu Li, Hangchao Li, Qi Liu, Huijie Dong, Bo Wang, Baodong Ye, Shenyun Lin, Yiping Shen, and Dijiong Wu. "Diagnosing MonoMAC Syndrome in GATA2 Germline Mutated Myelodysplastic Syndrome via Next-Generation Sequencing in a Patient with Refractory and Complex Infection: Case Report and Literature Review." Infection and Drug Resistance Volume 14 (April 2021): 1311–17. http://dx.doi.org/10.2147/idr.s305825.

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43

Nichols-Vinueza, Diana X., Nirali N. Shah, Jennifer Cuellar-Rodriguez, Thomas R. Bauer, Katherine R. Calvo, Luigi D. Notarangelo, Steven M. Holland, and Dennis D. Hickstein. "Allogeneic Hematopoietic Stem-Cell Transplantation in Patients with GATA 2 Deficiency: Influence of Donor Stem Cell Source and Post-Transplantation Cyclophosphamide." Blood 136, Supplement 1 (November 5, 2020): 37–38. http://dx.doi.org/10.1182/blood-2020-138535.

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Background: We recently reported on the single-institution experience with allogeneic hematopoietic stem cell transplantation (HSCT) in 22 consecutive patients with GATA2 deficiency or the MonoMAC syndrome and observed a disease-free survival of nearly 90%. However, despite 10/10 HLA match of matched related donors (MRD) and matched unrelated donors (URD), there was a 25% incidence of grades III-IV acute graft-versus-host disease (GVHD) with tacrolimus/methotrexate (Tacro/MTX). In contrast, there was no grade III-IV acute GVHD in the haploidentical related donor (HRD) recipients, all of whom received GVHD prophylaxis with post-transplantation cyclophosphamide (PT/Cy) followed by tacrolimus/mycophenolate (tacro/MMF). Based on this initial experience, the protocol was subsequently amended to incorporate PT/Cy in all patients. We now report on this expanded cohort of a total of 59 patients, representing the largest experience with HSCT for GATA2 deficiency. Methods: This single-institution study was conducted at the National Institutes of Health Clinical Center between 2013 and 2020 (ClinicalTrials.gov Identifier: NCT01861106). Patients between 12 to 60 years of age were eligible if they had a deleterious mutation in the GATA2 gene, or clinical picture of the MonoMAC syndrome. Although the primary endpoints were engraftment and reversal of the clinical phenotype, a secondary endpoint was added to determine if PT/Cy in the MRD and URD reduced the incidence of grade III-IV aGVHD without compromising the overall and disease-free survival. Immune reconstitution at 100 days, 6, 12, 24, 36 months was analyzed. Results: 59 patients (median age at diagnosis 24 years; IQR 20-32) with GATA2 deficiency or the MonoMAC syndrome underwent allogeneic HSCT. MRD and URD recipients received busulfan for four days (targeted to an AUC 3600-4800) and fludarabine, whereas HRD recipients received two days of low dose cyclophosphamide, 5 days fludarabine, 200cGY total body irradiation, and two or three days of busulfan depending upon the presence or absence of clonal cytogenetic abnormalities. Donor sources included: 11 MRD, 31 URD, and 17 HRD. Median follow-up was 2 years [IQR 1-4], 88% (52/59) are currently alive. Seven deaths have occurred, including: persistent AML (n=1); infection (n=4); poor graft function and cardiac arrest (n=1) and from HPV-associated metastatic cancer (n=1). All of the patients who received HRD transplant are alive. Median time to neutrophil engraftment was 15 days (IQR 13-17) and 19.5 days (IQR 16-25) for platelets. Ninety three percent (55/59) of patients had blood test results after 100 days post-transplant to assess immune reconstitution; eighty one percent (45/55) had normal absolute monocyte counts, 67% (37/55) had normal absolute NK cell counts and 89% (49/55) had normal B cells counts. There was one case of primary graft failure in a recipient of an URD-transplant, and one secondary graft rejection in a recipient of HRD-transplant. Fifty-four percent (32/59) of patients had pre-HSCT myelodysplastic syndrome (MDS), and only two relapsed post-HSCT. Forty two percent (25/59) had abnormal cytogenetics pre-HSCT; amongst 23 patients with serial pre/post bone marrow cytogenetic evaluations, 19 had established normal cytogenetics post-HSCT. Forty five percent (19/42) of MRD/URD patients received Tacro/MTX for GVHD prophylaxis, and 31.5% (6/19) developed grade III-IV acute GVHD (aGVHD). In contrast, 55% (23/42) MRD/URD patients received PT/Cy for GVHD prophylaxis, and none developed grade III-IV aGVHD (p 0.0052). Five percent (1/17) of HRD recipients developed grade III-IV aGVHD. Forty two percent (8/19) of MRD/URD patients who received post-transplant Tacro/MTX had chronic GVHD, 4.3% (1/23) of MRD/URD patients who received PT/Cy developed cGVHD, and 5.8% (1/17) of HRD patients developed cGVHD within the first 2 years post-transplant. Conclusions: Allogeneic HSCT using a busulfan-based regimen in GATA2 deficiency results in nearly a 90% disease-free survival with long-term immune reconstitution. The use of PT-Cy reduced the risk of severe aGVHD and cGVHD and did not increase the risk of relapse or progression of MDS/AML. With earlier recognition of the disease, and the use of PT/Cy more broadly, these results are expected to continue to improve. Disclosures Notarangelo: NIAID, NIH: Research Funding.

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Fazylov, S. D., O. A. Nurkenov, A. E. Arinova, A. M. Gazaliev, R. E. Bakirova, M. K. Ibraev, A. Т. Takibayeva та A. S. Fazylov. "INDICATORS OF CELL METABOLISM IN VITRO IN RESEARCHES OF ANTI-INFLAMMATORY AND CYTOTOXIC EFFECTS OF FULLEROPYRROLIDINES С60 AND THEIR INITIAL SUBSTRATES". BULLETIN 5, № 387 (15 жовтня 2020): 25–33. http://dx.doi.org/10.32014/2020.2518-1467.139.

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The article considers data on the in vitro study of new fulleropyrrolidine compounds for anti-inflammatory and cytotoxic activity in cultures of human monocyte cell lines MonoMac-6 and THP-1Blue and also as inhibitors of human neutrophil elastase. This enzyme is a regulator of inflammation. In different situations, it can act both as a pro-inflammatory and as an anti-inflammatory agent. An imbalance in the regulation of elastase activity plays an important role in the pathogenesis of cystic fibrosis, acute respiratory distress syndrome, bronchiectasis, chronic obstructive pulmonary disease, type 2 diabetes mellitus, atherosclerosis and hypertension. In the future, such studies should lead to the creation of optimal in vitro models that most adequately reflect the situation in vivo and establish the relationship between the structure and activity of the studied drugs. It is noted that the presence of lipophilic properties in fullerene C60 derivatives is especially important in the development of pharmaceuticals for the control of pathogens of various infectious diseases. Fullerene C60 derivatives have the ability to easily penetrate lipid membranes, overcome the blood-brain barrier, and modulate ion transport. Compounds were tested for anti-inflammatory and cytotoxic activity (in vitro) on cultures of human monocytic cell lines MonoMac-6 and THP-1Blue. Modified fullerene compounds of various structures were tested for their inhibitory ability against neutrophil elastase enzyme (in vitro). Elastase activity was evaluated by the ability of fulleropyrrolidine compounds to hydrolyze the synthetic substrate N-methylsuccinyl-Ala-Ala-Pro-Val-7-amino-4-me-thylcoumarin (Calbiochem). The results of studies of fullerene compounds in relation to their anti-inflammatory and cytotoxic activity are obtained. The analysis of the fluorescence kinetics of the compounds was carried out. The cytotoxic activity of the samples was investigated in the Brine Schrimp test using Artemia salina. All compounds have cytotoxicity, which suggests a lack of selectivity of chemotherapeutic action. In general, the presence of a cytotoxic effect confirms the reality of antimicrobial action. The results of the study of the antibacterial and antifungal activity of the synthesized new fulleropyrrolidines and their starting substrates are described (S. aureus 505, Bacillus subtilis, Str.agalactiae, E. Coli M-17, Ps.aeruginosa, Candida аlbicans, Penicillium citrinum, Aspergillus niger, Aspergillus flavus, Trichophyton mentagraphytos, Epidermophyton fioccosum). As a result of the study of the potential antifungal activity of the compounds, it was found that only two drugs inhibit the growth of test cultures in vitro. All other studied samples have practically no activity against the yeast fungi Candida albicans. In general, the presence of a cytotoxic effect in the studied fullerene compounds confirms the reality of the antimicrobial action.

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45

Sturgess, Katherine, Mary Slatter, Venetia Bigley, Muzlifah Haniffa, Xiao-Nong Wang, Rachel Dickinson, Naomi McGovern, et al. "Reduced Intensity Hematopoietic Stem Cell Transplant Rescues Immune Function and Corrects Pulmonary Alveolar Proteinosis in DCML Deficiency/GATA 2 Mutation." Blood 118, no. 21 (November 18, 2011): 2045. http://dx.doi.org/10.1182/blood.v118.21.2045.2045.

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Abstract Abstract 2045 The novel syndrome of Dendritic Cell, Monocyte, B and NK lymphocyte (DCML) deficiency has recently been characterised and found to be caused by mutations in the transcription factor GATA-2 (Dickinson et al. Blood 2011, Hsu et al. Blood 2011). In this report we describe a series of 10 patients and show that there is a high risk of death unless curative haematopoietic stem cell transplantation (HSCT) is performed. Our case series includes 10 patients; 4 sporadic cases and 6 cases from 2 pedigrees showing autosomal dominant inheritance. 7 patients died; of the 3 survivors, 2 were transplanted and show marked resolution of their disease with a follow up of 36 and 11 months, respectively. Causes of death in the patients who died include disseminated mycobacterium avium infection (2) H1N1 influenza (1) candidiasis (1) pulmonary alveolar proteinosis (2) and CMV pneumonitis (1). At least 8 patients had chronic HPV infection and 2 patients had autoimmune phenomena including inflammatory arthritis and erythema nodosum. One patient also developed lymphoma. All patients had monocytopenia and decreased B and NK cells with normal T cells at presentation. Haemoglobin, platelets and neutrophil counts were within normal ranges or mildly reduced. In 4 patients, near absolute dendritic cell (DC) deficiency and elevated Flt-3 ligand was also confirmed. BM aspirate showed dysplastic megakaryocytes and increased fibrosis in some instances. Macrophages were present in dermis, bone marrow and lung, epidermal Langerhans cells were largely preserved and plasma cells were found in inflammatory lesions by immunohistochemistry. GATA-2 mutation was confirmed by Sanger sequencing in all cases. Of the 2 patients treated with transplantation, the first patient presented aged 12 with disseminated BCG sepsis 6 months following BCG vaccination. Skin biopsy showed acid fast bacilli but no well-formed granulomata, and ongoing sepsis failed to respond to antitubercular therapy including addition of IFN gamma. The second patient presented to gynaecology services at the age of 20 with vulval intraepithelial neoplasia stage 3 (VIN3), and then to respiratory physicians a year later with breathlessness, productive cough, weight loss and night sweats; pulmonary alveolar proteinosis was diagnosed on biopsy. She continued to deteriorate despite whole lung lavage, and developed respiratory failure requiring 35% oxygen and nocturnal non-invasive ventilation (NIV). The patient's family history included two generations affected by haematological malignancy or respiratory illness in early adulthood, inherited in a fashion suggesting an autosomal dominant trait. Both patients underwent reduced intensity allogeneic haematopoietic stem cell transplantation with PBMC from unrelated adult donors (patient 1 – 10/12 HLA match; patient 2 – 9/12); transplant conditioning was with Fludarabine 150mg/m2, Melphalan 140mg/m2 and Alemtuzumab 60mg (patient 1), and Fludarabine 150mg/m2, Busulphan 6.4mg/kg, Alemtuzumab 60mg (patient 2). GVHD prophylaxis was with Ciclosporin and Mycophenolate Mofetil. Both transplants were uneventful. 32 months post-transplantation, patient 1 is well and off all medication. The monocyte count, lymphocyte subsets and immunoglobulins are normal and there were good responses to tetanus and HIB vaccinations. Chimerism shows 100% donor myeloid and B cells and 85% donor T cells. 9 months post-transplantation patient 2 has improved significantly and no longer requires oxygen or NIV. Lung function tests and radiology have significantly improved. Monocytes are in the normal range and chimerism shows 100% donor CD15 and 85% donor CD3. Follow-up continues with gynaecology for VIN3 associated with HPV16/18 infection. Neither patient has developed GVHD. Here we show that DCML deficiency caused by GATA-2 mutation incurs a high risk of mortality due to infection or respiratory failure unless treated by HSCT. Rapid correction of both immunodeficiency and pulmonary alveolar proteinosis is possible, even in the context of severe infection or respiratory failure, using reduced intensity conditioning. The absence of GVHD in both these cases, despite significant HLA-mismatching, may reflect the absence of recipient DC at transplantation. Disclosures: No relevant conflicts of interest to declare.

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Hewitt, Kyle, Kirby D. Johnson, Duk-Hyoung Kim, Prithvia Devadas, Rajalekshmi Prathibha, Chandler Zuo, Colin Dewey, et al. "Cistrome Control of Hematopoieitic Stem/Progenitor Cell Function." Blood 126, no. 23 (December 3, 2015): 43. http://dx.doi.org/10.1182/blood.v126.23.43.43.

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Abstract Cis-regulatory mechanisms control chromatin structure and cellular identity. At the GATA2 locus, two cis-elements are linked to human pathologies, including a primary immunodeficiency (MonoMAC syndrome) associated with multiple complex phenotypes, myelodysplastic syndrome, and acute myeloid leukemia (AML). Mutations that disrupt the function of an intronic GATA2 +9.5 element cause MonoMAC syndrome, while an inversion that relocates the distal GATA2 -77 element to the EVI1 locus induces AML. The +9.5 and -77 cis-elements are GATA-2-occupied and confer context-dependent enhancer activities in select hematopoietic cell types in vivo. In knockout mouse models, the Gata2 +9.5 cis-element is required for hematopoietic stem cell (HSC) genesis, whereas the Gata2 -77 cis-element governs a unique sector of the myeloid progenitor cell transcriptome without impacting HSC genesis. Three other GATA-2-occupied cis-elements (-1.8, -2.8 and -3.9) were not individually required for hematopoietic development, and had relatively mild effects on Gata2 expression; the -1.8 site was required to maintain Gata2 repression in late-stage erythroblasts, the -2.8 conferred maximal Gata2 expression, and the -3.9 had no effect on Gata2 expression. We predict that additional cis-elements exist in the genome with functions resembling the +9.5 and -77, and their analysis will provide important mechanistic and biological insights. We utilized the known properties of Gata2 cis-elements as learning tools to identify prospective constituents of a hematopoietic stem/progenitor cell (HSPC) regulatory cistrome genome-wide. Using sequence attributes shared with the critically-important +9.5 element, namely a CATCTG-8bp spacer-AGATAA, we generated a list of 797 candidate cis-elements ("+9.5-like" elements). This list was prioritized using chromatin occupancy by GATA-2 and Scl/TAL-1, among others, chromatin accessibility, evolutionary conservation, and histone modifications in a multitude of biologically-relevant cell types. Gene editing was used to delete three high-ranked elements (Samd14 +2.5, Bcl2l1 +12.2, and Dapp1 +23.5), revealing their importance for transcriptional activation, GATA-2 occupancy and chromatin accessibility, while deletion of two low-ranked elements (Mrps9 +17.6 and Mgmt +182) had no effect on gene transcription. One such cis-element (Samd14 +2.5) resided in Samd14, a gene with undescribed biological function. Samd14 has a conserved sterile α-motif and coiled-coil domain, and is highly expressed in hematopoietic progenitors and differentiated progeny. Mouse knockout of the Samd14 +2.5 element dramatically lowered expression of Samd14 in hematopoietic progenitors. We conducted loss-of-function analysis to elucidate Samd14 function in lineage-depleted (Lin-) E14.5 fetal liver cells infected with control or Samd14 shRNA-expressing retrovirus. In a CFU assay, Samd14 knockdown reduced BFU-E and CFU-GM colonies 3.4-fold. Early erythroid precursor R1 (CD71low, Ter119-) and R2 (CD71high, Ter119-) cell populations decreased ~2-fold, concomitant with increases in more mature R3 and R4/5 populations (Ter119+). In R1/R2 cells, Samd14 knockdown reduced surface c-Kit expression by 1.6-fold and prevented Stem Cell Factor/c-Kit activation of AKT. Cellular deficits resulting from Samd14 knockdown could be rescued by c-Kit. In -77-/- common myeloid progenitors, Samd14 was ~20-fold downregulated. Thus, the importance of Samd14 and the Samd14 +2.5 element on progenitor function and SCF/c-Kit signaling validates our strategy for identifying cis-elements relevant for hematopoiesis. Our findings demonstrate that +9.5-like elements control cell signaling (Samd14 +2.5) and apoptosis (Bcl2l1 +12.2), and we predict that additional cistrome constituents will control these and other important HSPC processes. I will discuss the mechanistic and biological properties of additional cis-elements analyzed from a cohort of 68 GATA-2-occupied elements and general principles arising from the HSPC cistrome analysis, which provide unique insights into the control of hematopoiesis and GATA-2-linked pathologies. Disclosures No relevant conflicts of interest to declare.

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47

Onodera, Koichi, Tohru Fujiwara, Yasushi Onishi, Ari Itoh-Nakadai, Yoko Okitsu, Noriko Fukuhara, Kenichi Ishizawa, Ritsuko Shimizu, Masayuki Yamamoto, and Hideo Harigae. "GATA-2 Regulates Dendritic Cell Differentiation." Blood 126, no. 23 (December 3, 2015): 2382. http://dx.doi.org/10.1182/blood.v126.23.2382.2382.

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Abstract (Background) Dendritic cells (DCs) are critical regulators of the immune response, but their differentiation mechanism remains unclear. Heterozygous germline GATA-2 mutations in humans cause MonoMAC syndrome, characterized by monocytopenia and predisposition to myelodysplasia/acute myeloid leukemia. In this syndrome, DC count decreases profoundly, with an increased susceptibility to viral infections, impaired phagocytosis, and decreased cytokine production. In the present study, we analyzed the role of GATA-2 in DC differentiation and the underlying molecular mechanisms. (Method) Gata2 haploinsufficient mice (Gata2+/−: Tsai et al. Nature 1994) and tamoxifen-inducible Gata2-knockout mice (Gata2flox/flox/ER-Cre: Charles et al. Molecular Endocrinology 2006) were used. To generate conditional Gata2 knockouts in vivo, Gata2flox/flox/ER-Cre mice were intraperitoneally injected with 1-μg tamoxifen on days 1-3 and 8-10 and evaluated on days 20-22. Isolation of splenic DCs and bone marrow (BM) precursors, including LSK (Lin- Sca1+ Kit+ cell), CMP (common myeloid-restricted progenitor), GMP (granulocyte-macrophage progenitor), CLP (common lymphoid-restricted progenitor), and CDP (common dendritic cell precursor), were separated with both MACS (Miltenyi Biotech) and BD FACSAria II (BD Biosciences). For the in vitro analysis of Gata2-knockout, BM cells were cultured with CD45.1+ BM feeder cells from SJL mice (The Jackson Laboratory) with FLT3L (200 ng/mL) and 4-hydroxytamoxifen (Sigma). For transcription profiling, SurePrint G3 mouse GE microarray (Agilent) was used, and the data was subsequently analyzed with ImmGen database (http://www.immgen.org). Promoter assay was conducted with Dual Luciferase Reporter Assay system (Promega). Quantitative chromatin immunoprecipitation (ChIP) analysis was performed using CMP fraction and erythroid-myeloid-lymphoid (EML) hematopoietic precursor cell line (ATCC) with antibodies to GATA-2 (sc-9008, Santa Cruz Biotechnology). (Results) Quantitative RT-PCR analysis showed abundant Gata2 expression in LSK and CMP fractions, with detectable expression in GMP, CLP, and CDP fractions and in vitro differentiated DCs. Although the DC count did not change in Gata2 haploinsufficient mice, it significantly and profoundly decreased in Gata2 conditional knockout mice. To examine the role of GATA-2 during DC differentiation, we knocked out Gata2 during in vitro DC differentiation, starting from LSK, CMP, GMP, CLP, and CDP fractions obtained from Gata2flox/flox/ER-Cre mice. Gata2 knockout significantly decreased CD11c+ DC counts from LSK, CMP, and CDP fractions, while those from CLP and GMP were unaffected, implying the importance of GATA-2 during DC differentiation in the pathway from LSK to CDP via CMP, not via CLP nor GMP. To elucidate the underlying molecular mechanisms, we performed expression profiling with control and Gata2 -knockout DC progenitors from CMP of Gata2flox/flox/ER-Cre mice. Gata2 knockout caused >5-fold upregulation and downregulation of 67 and 63 genes, respectively. Although genes critical for the DC differentiation, e.g., Spi1, Ikzf1, and Gfi1, were not detected among the GATA-2-regulated gene ensemble, we found significant enrichment of myeloid-related and T lymphocyte-related genes among the downregulated and upregulated gene ensembles, respectively. We focused on Gata3 upregulation (7.33-fold) as a potential key mechanism contributing to Gata2 knockout-related impaired DC differentiation. Quantitative ChIP analysis with both CMP fraction and EML cell line demonstrated obvious GATA-2 chromatin occupancy at the consensus GATA-binding motif within Gata3+190 kb, which was conserved with human. Furthermore, addition of Gata3 +190 kb region to the Gata3 promoter (~0.5 kb) significantly decreased luciferase activity, which was significantly recovered by the deletion of GATA sequence within Gata3 +190 kb, in EML cells. (Conclusion) GATA-2 seems to play an important role for cell fate specification toward myeloid versus T lymphocytes, and thus contributing to the DC differentiation. Our data offer a better understanding of the pathophysiology of MonoMAC syndrome. Disclosures Fujiwara: Chugai Pharmaceuticals. Co., Ltd.: Research Funding. Fukuhara:Gilead Sciences: Research Funding. Ishizawa:GSK: Research Funding; Takeda: Research Funding; Celgin: Speakers Bureau; Kyowa Kirin: Research Funding; Celgin: Research Funding; Janssen: Research Funding; Takeda: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Pfizer: Speakers Bureau.

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48

Hahn, Christopher N., Simone K. Feurstein, Deepak Singhal, Monika M. Kutyna, Rakchha Chhetri, Amilia Wee, Daniel Thomas, Hamish S. Scott, and Devendra Hiwase. "Unexpected High Frequency of Pathogenic Germline Variants in Older Adults with Primary Myelodysplastic Syndrome." Blood 138, Supplement 1 (November 5, 2021): 2594. http://dx.doi.org/10.1182/blood-2021-154514.

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Abstract Background: Germline predisposition is increasingly being recognised in myeloid neoplasms (MN) including primary myelodysplastic syndrome. An unequivocal diagnosis of germline predisposition carries actionable considerations for patient management including donor stem cell source for allogeneic transplantation, dose-reduction of conditioning regimes and screening for extra-hematological disease (such as pulmonary abnormalities in patients with telomere biology disorders). In addition, the identification of MDS predisposition syndromes can avoid misdiagnosis (for example, distinguishing idiopathic thrombocytopenic purpura from thrombocytopenia due to RUNX1 germline variant). However, the prevalence of pathogenic germline variants (PGVs) in unselected pMDS patients presenting at older age remains unknown. Aim: This study assesses frequency and type of pathogenic germline variants in MDS patients and compares with age matched healthy controls and patients with other cancers. Method: We analysed 68 known cancer predisposition genes in germline samples of 146 samples from myeloid neoplasms. Study included primary MDS (n=51) and MDS diagnosed in cancer survivors with (n=77) or without prior exposure to cytotoxic therapy (n=18). Using uniform American College of Medical Genetics and Genomics (ACMG) guidelines for annotating germline mutation, we also compared the frequency of pathogenic germline variants in the same genes with patients with single cancer and age-match healthy controls (>70 years). Results: Pathogenic germline variants (PGVs) were identified in 19% (28/146) patients compared to 4% and 3% patients with single cancer and age-matched controls respectively (P<0.0001) (Fig. 1A). Median age at diagnosis was similar between MN patients with or without PGVs [66 years (19-81) vs. 70 years (33-87); P=0.06]. PGVs were most frequent in DDX41 (n=7, 33%) followed by BRCA1 (n=2, 10%), GATA2 (n=2; 10%) and TP53 (n=2; 10%) (Fig.1B). We also identified pathogenic copy number variations (CNV) in 4 patients. The distribution of PGVs was also different, with DDX41 PGVs absent in single cancers and more prevalent in MN than age-matched controls (35% vs. 4%, P<0.001). The frequency of PGV was not significantly different between P-MN and T-MN/ MC-MN (17% versus 10%, P = 0.32 (Fig.1C). The frequency of PGV was 30%, 6%, 19%, 15% and 18% in patients ≤50, 51-59, 60-69, 70-79 and >80 years of age (Fig. 1D). Phenotypic features such as monocytopenia and mycobacterium infections (MonoMAC; SA460) and personal and family history of pulmonary fibrosis (SA918) were present in only two cases with PGVs. Family history of MDS/AML was present in only in four cases with PGVs, in which PGVs were found in typical myeloid malignancy genes (DDX41, GATA2). Importantly, some patients with family history of solid cancers carried PGVs in genes traditionally associated with solid cancers (e.g. MSH6, NF1, TP53 and BRCA1). SA927 had a PGV in MSH6 and multiple first-degree relatives with solid cancers including colon, renal and brain cancers. Moreover, 41% of adults with hematological disorders and a personal and/or family history of interstitial lung disease had PGVs in telomere biology disorder genes. Hence, family history should not be restricted to hematological disorders, but also solid cancers and non-malignant phenotypes (e.g. hepatic and pulmonary fibrosis). The frequency of PGVs was not different in patients with and without family history of cancer (23% vs. 13%, P=0.32). Conclusion: The frequency of PGVs is significantly high in MN compared to age matched healthy control and other cancer patients. Our observation of a high frequency of PGVs in the older MDS population warrants standardization of germline testing at diagnosis to guide optimal management of patients and their families. Figure 1 Figure 1. Disclosures Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

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Holland, Steven M. "Novel Defects in Host Defense Evinced As Nontuberculous Mycobacterial and Dimorphic Mold Infections: GATA2 Deficiency, STAT1 Mutations, Anticytokine Autoantibodies." Blood 118, no. 21 (November 18, 2011): SCI—20—SCI—20. http://dx.doi.org/10.1182/blood.v118.21.sci-20.sci-20.

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Abstract Abstract SCI-20 Nontuberculous mycobacteria are relatively ubiquitous organisms of low virulence, disseminated infection with which suggests an underlying defect in host defense. Dimorphic molds (e.g., histoplasmosis, coccidioidomycosis, penicilliosis) are regionally limited and cause severe infections only in the immune compromised. We have focused on severe cases of these infections to identify genetic and acquired syndromes of immune deficiency that have not been previously recognized. 1. The syndrome of monocytopenia, NK, and B cell lymphopenia and lack of circulating dendritic cells is associated with severe infections with mycobacteria, dimorphic molds, human papilloma virus, and molluscum cantagiosum. These patients also develop myelodysplasia and pulmonary alveolar proteinosis and may progress to frank leukemia. Mutations in GATA2 are responsible for the syndrome (monoMAC for monocytopenia and M. avium complex infection). Hematopathologically, patients have micromegakaryocytes and cytogenetic abnormalities, most commonly monosomy 7 and trisomy 8. Both protein-positive and protein-negative heterozygous mutations have been identified, suggesting that haploinsufficiency is a unifying cause of disease. The spectrum of pathologic mutations is broad and likely extends into phenotypes that are distinct from those recognized initially. 2. Mutations in STAT1 have been associated with mycobacterial disease (dominant negative inhibitory), fatal viral and bacterial disease (recessive), and mucocutaneous candidiasis (dominant gain of function). We have identified distinct and independent STAT1 mutations in three patients that have led to severe, refractory disseminated coccidioidomycosis or histoplasmosis. These mutations lead to hypomethylation of STAT1, which leads to its persistent hyperphosphorylation, and impairment of restimulation activity. These mutations are important because they lie in the same plane of the molecule and cause severe invasive dimorphic yeast infections. 3. Autoantibodies are common, especially in adult women. We have previously recognized East Asia-born adult women living in the United States who have high titer autoantibodies to interferon gamma (IFNγ). We have recently recognized large cohorts of similar patients in Thailand and Taiwan and conducted a prospective trial of their phenotype and the presence and type of anti-IFNγ autoantibodies. We found a significant population of patients with disseminated nontuberculous mycobacterial infections (but not tuberculosis), salmonella, cryptococcosis, histoplasmosis, or varicella zoster in Asia whose sole identifiable risk factor was extremely elevated anti-IFNγ autoantibodies. We have characterized the severity of the blockade and the subclass of the antibodies and explored the rate in several control populations as well. These apparently adult-onset acquired autoantibodies profoundly inhibit IFNγ signaling, leading to infections with IFNγ-responsive organisms. These emerging syndromes cross the lines of infectious disease, cancer, and rheumatology. Disclosures: No relevant conflicts of interest to declare.

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Dokal, Inderjeet. "Overlap of Syndromes Associated with Myelodysplasia and Leukemia." Blood 124, no. 21 (December 6, 2014): SCI—32—SCI—32. http://dx.doi.org/10.1182/blood.v124.21.sci-32.sci-32.

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Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are heterogeneous hematopoietic stem cell clonal disorders characterized by defective hematopoiesis and premature mortality in many patients. The majority of MDS and AML cases are sporadic but there are also rare cases where two or more affected individuals are found within the same family - “familial myelodysplasia and leukemia.” These familial cases represent a high-risk group of patients who require a unique management approach; they also provide an excellent opportunity for the identification of genetic changes that drive the disease. Over the last 15 years several genetic subtypes of familial MDS/AML have been identified and characterized. This includes families with constitutional heterozygous mutations in RUNX1, CEBPA, TERC, TERT, GATA2, and SRP72. The spectrum of mutations associated with familial MDS/AML implicates different biological pathways in the development of the disease, including transcription regulation (RUNX1, CEBPA and GATA2), telomere maintenance (TERC and TERT) and signal recognition (SRP72). It is notable that somatic mutations in RUNX1, CEBPA, and GATA2 are found in patients with sporadic MDS and AML. These discoveries demonstrate that familial MDS/AML is very heterogeneous and that the genetic characterization of the uncharacterized families will offer further insight into the primary pathophysiology of MDS/AML. Analysis of the MDS/AML families demonstrates considerable variability in the spectrum of features seen in these six genetic categories. There is heterogeneity even within each genetic subtype. The diverse range of different mutations in the disease gene in part explains the phenotypic difference between families. However, there are also differences amongst members of the same family (for example, in RUNX1 families some individuals only have a platelet abnormality and yet others have AML), suggesting that additional factors contribute to the phenotype. The mechanisms that underlie the development of progression to leukemia remain to be characterized. In families with CEBPA mutations there appears to be a near complete penetrance to developing AML. This is in contrast to the very diverse phenotypes associated with constitutional TERC and TERT mutations, ranging from dyskeratosis congenita (DC) to aplastic anemia, MDS, and AML. A similar situation has been observed with constitutional heterozygous GATA2 mutations. Here again affected individuals can display a wide range of phenotypes including MDS, AML, Emberger syndrome (primary lymphoedema with MDS/AML), MonoMAC syndrome (monocytopenia and Mycobacterium infection; the phenotype may also include Natural Killer cell and B-cell lymphopenia). It is notable that Natural Killer and B-cell deficiencies are also observed in DC. This highlights the overlap of features between the different genetic subtypes in addition to MDS/AML. Recognition of familial MDS/AML is important in guiding management. This includes appropriate genetic counselling of family members as well as careful selection of family donors regarding hematopoietic stem cell transplantation (HSCT). It also enables other specific modifications in the management. For example, patients with significant lymphopenia (be at secondary to TERC or GATA2 mutation) benefit from appropriate antimicrobial prophylaxis. Equally, patients with TERC and TERT mutations require low intensity Fludarabine-based HSCT (due to the abnormal/delayed healing of tissues as a consequence of the telomere deficiency) whereas patients with RUNX1 mutations appear to tolerate standard conditioning regimens. Further understanding of the biology and the associated phenotypic diversity will help to improve management of this group of patients. It is also likely to have relevance for sporadic MDS and AML. Disclosures No relevant conflicts of interest to declare.

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