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1
Piazza, Rocco, Sara Redaelli, Simona Valletta, Alessandra Pirola, Roberta Spinelli, Vera Magistroni, Dong-Wook Kim, Nicholas C. P. Cross, and Carlo Gambacorti-Passerini. "SETBP1 and CSF3R Mutations In Atypical Chronic Myeloid Leukemia." Blood 122, no. 21 (November 15, 2013): 2598. http://dx.doi.org/10.1182/blood.v122.21.2598.2598.
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Abstract Atypical Chronic Myeloid Leukemia (aCML) is a clonal disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes. In aCML many clinical features suggest the diagnosis of CML, however the lack of the BCR-ABL1 fusion point to a different pathogenetic process. Recently, we identified the presence of clonal somatic mutations occurring in the SETBP1 gene in approximately 25% of aCML samples (Piazza R. et al., Nat Genet. 2013 Jan;45(1):18-24). A subsequent study (Maxson J. et al., N Engl J Med. 2013 May 9;368(19):1781-90) demonstrated the presence of somatic mutations of the CSF3R gene in Chronic Neutrophilic Leukemia (CNL) and, with lower frequency, in aCML. In a recent follow-up of the first study (Gotlib J. et al., Blood. 2013 Jul 29), the presence of both CSF3R and SETBP1 variants was tested in a cohort of 9 CNL and 20 aCML cases, demonstrating the presence of CSF3R somatic mutations in 40% of the aCML patients. Of these mutations, 20% were membrane, 5% truncating and 15% compound variants. Interestingly, 5% of the aCML patients showed coexistence of CSF3R and SETBP1 mutations, suggesting that variants occurring in these genes are not mutually exclusive. To gain further insight into the relationship between CSF3R and SETBP1 in aCML, we extended our initial study by analyzing an expanded cohort of 65 aCML plus a total of 230 AML, ALL, CLL, CML, PV, TE, MMM, CMML and MDS cases for the presence of CSF3R and SETBP1 mutations. In line with previous findings (Piazza R. et al., Nat Genet. 2013 Jan;45(1):18-24; Maxson J. et al., N Engl J Med. 2013 May 9;368(19):1781-90), we found evidence of SETBP1 and/or CSF3R mutations only in MDS/MPN disorders. In aCML we identified a total of 18 (27.7%) mutations occurring in SETBP1 and 8 (12.3%) in the CSF3R gene. A large fraction (94.4 %) of the SETBP1 mutations was clustered in a 14 amino acid stretch that is also mutated in the Schinzel-Giedion syndrome, as previously reported (Piazza R. et al., Nat Genet. 2013 Jan;45(1):18-24). Of the 8 CSF3R mutations 5 were membrane proximal (4 T618I and 1 T615A) and 3 were truncating (2 Q776X and 1 Q781X). In 2 aCML samples we detected the coexistence of CSF3R and SETBP1 mutations. In both cases the CSF3R variant was a membrane proximal mutation; CSF3R and SETBP1 mutations were at comparable levels at the time of detection, therefore no conclusion can be drawn about the timing of the two mutational events. Taken globally these data indicate that somatic mutations occurring in SETBP1 and CSF3R are present in aCML and can coexist. Interestingly, the frequency of the CSF3R mutations in our aCML cohort is largely different from that of Maxson and colleagues (12.3 vs 40%), although the frequency of the combined CSF3R/SETBP1 mutations is similar (3.1 vs 5%): the reasons for this discrepancy are actually unclear. Previously we demonstrated that the presence of SETBP1 mutations in aCML is an independent negative prognostic factor (Piazza R. et al., Nat Genet. 2013 Jan;45(1):18-24). Further studies with larger cohorts will be required to assess the prognostic impact of concurrent SETBP1 and CSF3R mutations. Disclosures: Cross: Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Gambacorti-Passerini:Pfizer, BMS: Consultancy, Consultancy Other; Pfizer: Research Funding.
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Huard, Carine, Guy Miranda, Yulia Redko, Fran�oise Wessner, Simon J. Foster, and Marie-Pierre Chapot-Chartier. "Analysis of the Peptidoglycan Hydrolase Complement of Lactococcus lactis: Identification of a Third N-Acetylglucosaminidase, AcmC." Applied and Environmental Microbiology 70, no. 6 (June 2004): 3493–99. http://dx.doi.org/10.1128/aem.70.6.3493-3499.2004.
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ABSTRACT The peptidoglycan hydrolase (PGH) complement of Lactococcus lactis was identified by amino acid sequence similarity searching of the L. lactis IL-1403 complete genome sequence. Five PGHs that are not encoded by prophages were detected, including the previously characterized AcmA and AcmB proteins. Four of these PGHs, AcmA to AcmD, contain a catalytic domain homologous to that of enterococcal muramidase, but they have different domain structures. The fifth one (YjgB) has sequence similarity with the active-site domain of peptidoglycan-specific endopeptidases. The three new PGH-encoding genes identified in this study are all actively transcribed in L. lactis subsp. cremoris MG1363. The relative abundance of their transcripts varied during growth and was maximal during the early exponential growth phase. The three encoded proteins have peptidoglycan-hydrolyzing activities which are detected only at acidic pHs by zymography. Like AcmA and AcmB, AcmC has N-acetylglucosaminidase activity rather than the N-acetylmuramidase activity predicted by sequence similarity.
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Crisà, Elena, Maura Nicolosi, Valentina Ferri, Chiara Favini, Gianluca Gaidano, and Andrea Patriarca. "Atypical Chronic Myeloid Leukemia: Where Are We Now?" International Journal of Molecular Sciences 21, no. 18 (September 18, 2020): 6862. http://dx.doi.org/10.3390/ijms21186862.
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Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (>20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (< 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options.
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Dao, Kim-Hien T., and Jeffrey W. Tyner. "What's different about atypical CML and chronic neutrophilic leukemia?" Hematology 2015, no. 1 (December 5, 2015): 264–71. http://dx.doi.org/10.1182/asheducation-2015.1.264.
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Abstract Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare myeloid neoplasms defined largely by morphologic criteria. The discovery of CSF3R mutations in aCML and CNL have prompted a more comprehensive genetic profiling of these disorders. These studies have revealed aCML to be a genetically more heterogeneous disease than CNL, however, several groups have reported that SETBP1 and ASXL1 mutations occur at a high frequency and carry prognostic value in both diseases. We also report a novel finding—our study reveals a high frequency of U2AF1 mutations at codon Q157 associated with CSF3R mutant myeloid neoplasms. Collectively, these findings will refine the WHO diagnostic criteria of aCML and CNL and help us understand the genetic lesions and dysregulated signaling pathways contributing to disease development. Novel therapies that emerge from these genetic findings will need to be investigated in the setting of a clinical trial to determine the safety and efficacy of targeting various oncogenic drivers, such as JAK1/2 inhibition in CSF3R-T618I–positive aCML and CNL. In summary, recent advances in the genetic characterization of CNL and aCML are instrumental toward the development of new lines of therapy for these rare leukemias that lack an established standard of care and are historically associated with a poor prognosis.
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Gambacorti-Passerini, Carlo, Simona Valletta, Nils Winkelmann, Sara Redaelli, Roberta Spinelli, Alessandra Pirola, Laura Antolini, et al. "Recurrent SETBP1 Mutations in Atypical Chronic Myeloid Leukemia Abrogate an Ubiquitination Site and Dysregulate SETBP1 Protein Levels." Blood 120, no. 21 (November 16, 2012): LBA—2—LBA—2. http://dx.doi.org/10.1182/blood.v120.21.lba-2.lba-2.
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Abstract Abstract LBA-2 The SETBP1 gene codes for a predominantly nuclear protein with a predicted MW of 170 kD. Germline mutations of SETBP1 were described in patients affected by the Schinzel-Giedion syndrome (SGS), a rare disease characterized by bone, muscle and cardiac abnormalities, and presenting neuroepithelial neoplasms. In an effort to investigate the molecular pathogenesis of myeloid malignancies we applied a HTS strategy, including both exome sequencing and RNA-SEQ, to atypical Chronic Myeloid Leukemia (aCML), as defined by WHO criteria, with the aim of identifying novel recurrent driver mutations. aCML shares clinical and laboratory features with CML, but it lacks the pathognomonic BCR-ABL1fusion. Since no specific recurrent genomic or karyotypic abnormalities have been identified in aCML, the molecular pathogenesis of this disease has remained elusive and the outcome dismal (median survival 37 months) with no improvement over the last 20 years. This sharply contrasts with the outcome for CML, for which the prognosis was dramatically improved by the development of imatinib as a specific inhibitor of the BCR/ABL protein. Whole-exome sequencing of 9 aCML patients revealed the presence of 62 unique mutations (range 5–14 per patient), including a recurrent alteration of SETBP1 (G870S and D868N) in three cases. Targeted resequencing performed in 70 aCMLs, 574 patients with different hematological malignancies and 344 cell lines, identified SETBP1 mutations in 17 of 70 aCML patients (24.3%; 95% CI: 16–35%), 4 of 30 (13%) MDS/MPN-u and 3 of 82 (3.6%) CMML patients. Patients with mutations had higher white blood cell counts (p=0.008) and worse prognosis (p=0.01) when tested in multivariate analysis. TF1 cells transfected with SETBP1G870S showed increased SET levels, decreased PP2A activity and increased proliferation rates. The vast majority of mutations (85%) was located between residues 858 and 871, in the SKI homologous region of SETBP1, and were identical to germline changes seen in patients with SGS. This region may be critical for ubiquitin binding and for subsequent protein degradation, since the Eukaryotic Linear Motif (ELM) identified with high probability score a putative functional site (aa. 868–873) for beta-TrCP, the substrate recognition subunit of the E3 ubiquitin ligase. This prediction was experimentally validated using biotinylated, phosphorylated peptides encompassing this region (aa 859–879): while the wild type peptide could efficiently bind beta-TrCP as predicted, a peptide presenting the G870S mutation was incapable of binding this E3 ligase subunit, indicating a possible alteration in SETBP1 protein stability caused by this mutation. In agreement with these findings, cells transfected with SETBP1G870Sshowed increased levels of SETBP1 protein when compared to cells with similar expression levels of the wild type gene. Finally, RNA-SEQ yielded gene expression profiles with overrepresentation of genes under the control of Transforming Growth Factor Beta 1 (TGFβ1) among genes differentially expressed between SETBP1-mutated and unmutated aCML patients. Mutated SETBP1 represents a novel type of oncogene which is specifically present in aCML and closely related diseases. These data allow for a better understanding of the molecular pathogenesis of this disease; they provide evidence that SETBP1 mutations might be a new biomarker for future diagnosis and classification of aCML and related diseases, and indicate a potential strategy to develop new treatment modalities for malignancies caused by mutated SETBP1. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.
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Raizada, N., T. Sagar, and S. Ramanan. "Comparative study of safety and efficacy of imatinib mesylate therapy in pediatric and adult chronic myeloid leukemia." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 20016. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.20016.
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20016 Background: Chronic Myeloid Leukemia (CML) is one of the rare pediatric cancers. Imatinib is now the standard of care in adult CML (ACML) with newer compounds being investigated to overcome the burden of Imatinib resistance. Pediatric CML (PCML) has been an area little explored and effective strategies are not yet defined. Although, allogenic hematopoietic stem cell transplantation (HSCT) still remains the gold-standard treatment, the choice of drug in the subset in which HSCT is not a suitable option remains to be determined. Methods: This was a single-institution prospective study conducted from April 2004-March 2006, analyzing and comparing 293 Philadelphia chromosome (PH) positive CML patients in pediatric and adolescent subsets (i.e. age =18 years) not eligible for allogenic HSCT with ACML. After obtaining a written informed consent, a starting dose of 400 mg/m2/d Imatinib mesylate was administered in adults, whereas in pediatric and adolescents it was 400 mg/m2/d if the body surface area (BSA) was <1 m2, or 400 mg/d if BSA was >1m2. Results: 27 patients were in the age group =18 years; male to female ratio was 1.07:1. Gender ratio in 266 ACML patients showed a male preponderance (2.5:1). The mean age in ACML was 37.4 years. In pediatric subsets, a trend toward CML in adolescents was observed with mean age 14.85 years. Majority of the patients were in chronic phase (81.5% PCML and 85.7% ACML) with overall 93% patients receiving prior hydroxyurea as a cytoreductive agent. An unusual finding was higher incidence of Hypodiploidy (significance undetermined) and 5 patients had double PH. 80.1% ACML patients achieved complete hematological response, but it was significantly lower (59.3%) in PCML. 39.5% ACML achieved major cytogenetic response which was less than most published western data. Hematologic and non-hematologic toxicities (GI, dermatological etc) were found to be higher in ACML. Low toxicities in PCML were attributed to good tolerance to Imatinib therapy; however a higher dropout rate in pediatric subsets was possibly due to poor social and parental support. Conclusion: We conclude that imatinib mesylate is both safe and efficacious drug for ACML, however further research is warranted in pediatric and adolescent population to establish its efficacy. No significant financial relationships to disclose.
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Kahleifeh, Zachary, and Himanshu Thapliyal. "EE-ACML: Energy-Efficient Adiabatic CMOS/MTJ Logic for CPA-Resistant IoT Devices." Sensors 21, no. 22 (November 18, 2021): 7651. http://dx.doi.org/10.3390/s21227651.
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Internet of Things (IoT) devices have strict energy constraints as they often operate on a battery supply. The cryptographic operations within IoT devices consume substantial energy and are vulnerable to a class of hardware attacks known as side-channel attacks. To reduce the energy consumption and defend against side-channel attacks, we propose combining adiabatic logic and Magnetic Tunnel Junctions to form our novel Energy Efficient-Adiabatic CMOS/MTJ Logic (EE-ACML). EE-ACML is shown to be both low energy and secure when compared to existing CMOS/MTJ architectures. EE-ACML reduces dynamic energy consumption with adiabatic logic, while MTJs reduce the leakage power of a circuit. To show practical functionality and energy savings, we designed one round of PRESENT-80 with the proposed EE-ACML integrated with an adiabatic clock generator. The proposed EE-ACML-based PRESENT-80 showed energy savings of 67.24% at 25 MHz and 86.5% at 100 MHz when compared with a previously proposed CMOS/MTJ circuit. Furthermore, we performed a CPA attack on our proposed design, and the key was kept secret.
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Redaelli, Sara, Rocco Piazza, Alessandra Pirola, Vera Magistroni, Susanne Schnittger, Manja Meggendorfer, Nicholas C. P. Cross, Delphine Rea, and Carlo Gambacorti-Passerini. "Recurrent KIT D816V Mutation in Atypical Chronic Myeloid Leukemia." Blood 124, no. 21 (December 6, 2014): 3576. http://dx.doi.org/10.1182/blood.v124.21.3576.3576.
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Abstract INTRODUCTION: Atypical Chronic Myeloid Leukemia (aCML) is a heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative syndromes, characterized by a poor prognosis with a median survival time of 37 months. In 2013, by applying Next Generation Sequencing (NGS) technologies on 8 aCML cases, we demonstrated the presence of a recurrent somatic mutations in the SETBP1 gene (Piazza et al, Nat Gen 2013). SETBP1 mutations were identified in approximately 30% of aCML cases. AIM: To further characterize the molecular pathogenesis of aCML and to possibly identify other recurrent lesions responsible for SETBP1 unmutated cases, we extended our initial NGS effort: we applied whole-exome and transcriptome sequencing to a total of 16 matched samples taken at onset of the disease. MATERIAL and METHODS: Whole-exome and transcriptome sequencing data were generated using an Illumina Genome Analyzer IIx following standard library-preparation protocols. Alignment to the reference GRCh37/hg19 genome was performed using BWA. Alignment data were processed using Samtools. Single nucleotide and small indel detection was performed using in-house software. Copy number analyses from whole-exome data were generated using CEQer (Piazza et al, PLoS One 2013) and gene fusions transcriptome data were screened using FusionAnalyser (Piazza et al, Nucleic Acids Res. 2012). RESULTS: The application of NGS techniques to the cohort of aCML cases led to the identification of a somatic, non-synonymous single-nucleotide mutation (chr4:g.55599321A>T) in the KIT gene in 1/16 (6%) cases. At protein level this mutation translated into the D816V variant that has been already described in several clonal disorders, such as systemic mastocytosis, gastrointestinal stromal tumors and acute myeloid leukemia. To assess whether the mutation identified by NGS was recurrent, we extended our analysis by targeted resequencing on a larger cohort of 68 aCML cases. This analysis revealed the presence of KIT mutations in 3 additional patients, thus confirming the recurrence of KIT variants in aCML. All the KIT mutations identified correspond to the D816V that is responsible for the constitutive activation of the tyrosine kinase. This finding suggests that the activation of the KIT tyrosine kinase signaling may play an important role in this subset of aCML patients. It is known from the literature that KIT D816V is highly sensitive to the tyrosine kinase inhibitor dasatinib (Schittenhelm MM, Cancer Res 2006). To test whether dasatinib is able to affect the growth of the leukemic clone in KIT mutated aCML cases, we performed ex vivo tritiated thymidine proliferation assays on bone marrow (BM) cells from one of the KIT D816V positive aCML patients in presence of either dasatinib, imatinib or vehicle alone: the proliferation assay showed that dasatinib was able to inhibit the proliferation of the leukemic clone with an IC50 of 1nM, while, as expected, neither imatinib nor vehicle alone were able to significantly impair cell growth. In line with these data, western blot with an anti- Phospho-KIT antibody on KIT+ lysates after treatment with increasing concentration of dasatinib showed that the drug was highly effective in inhibiting KIT autophosphorylation. To further confirm the inhibitory activity of dasatinib, we performed a colony assay on peripheral blood cells from a KIT D816V positive aCML patient grown in presence of increasing concentrations of the drug: treatment with 100nM dasatinib was able to completely inhibit cell growth, leading to a virtually complete absence of colonies in the D816V-positive plates. CONCLUSION: These data indicate that KIT D816V is a pro-oncogenic lesion recurrently present in aCML, albeit with low frequency (5/84, 6%) and that aCML cells bearing this mutation are highly sensitive to dasatinib, at least ex vivo. Given the very poor prognosis of this disorder, these findings suggest a new, highly efficient targeted treatment for a subset of aCML patients. Disclosures Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Meggendorfer:MLL Munich Leukemia Laboratory: Employment.
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Nam, Myung-Hyun, Ju-Yeon Kim, Soo-Young Yoon, Chae Seung Lim, Chang Kyu Lee, Yunjung Cho, Young-Kee Kim, and Kap No Lee. "JAK2 V617F Mutation In Atypical Chronic Myeloid Leukemia." Blood 116, no. 21 (November 19, 2010): 5069. http://dx.doi.org/10.1182/blood.v116.21.5069.5069.
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Abstract Abstract 5069 Atypical chronic myeloid leukemia (aCML) is a rare leukemic disorder which shows myelodysplastic and myeloproliferative features simultaneously. Some cases of JAK2 V617F mutation in aCML were reported before WHO criteria introduced (Jelinek J et al. Blood 2005; Jones AV et al. Blood 2005; Levine RL et al. Blood 2005). However, Fend F et al observed no JAK2 V617F mutation in aCML as defined by WHO classification (Fend F et al. Leuk Res 2008), which result was refuted by a case report (Campiotti L et al. Leuk Res 2009). Here we analyzed JAK2 V617F mutation with amplification refractory mutation system (ARMS) and direct sequencing in three cases of aCML and found a case with JAK2 V617F mutation. All three cases were diagnosed as aCML according to WHO classification and showed significant myelodysplastic/myeloproliferative features in peripheral blood and bone marrow aspirates. Absence of BCR/ABL1 gene rearrangement was confirmed by FISH analysis, and conventional cytogenetic analysis revealed trisomy 8 in a case with no JAK2 V617F mutation. The patient with JAK2 V617F mutation poorly responds with hydroxyurea therapy and is showing prolonged leukocytosis. Disclosures: No relevant conflicts of interest to declare.
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Schauwecker, Florian, Frank Pfennig, Werner Schröder, and Ullrich Keller. "Molecular Cloning of the Actinomycin Synthetase Gene Cluster from Streptomyces chrysomallus and Functional Heterologous Expression of the Gene Encoding Actinomycin Synthetase II." Journal of Bacteriology 180, no. 9 (May 1, 1998): 2468–74. http://dx.doi.org/10.1128/jb.180.9.2468-2474.1998.
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ABSTRACT The actinomycin synthetases ACMS I, II, and III catalyze the assembly of the acyl peptide lactone precursor of actinomycin by a nonribosomal mechanism. We have cloned the genes of ACMS I (acmA) and ACMS II (acmB) by hybridization screening of a cosmid library of Streptomyces chrysomallusDNA with synthetic oligonucleotides derived from peptide sequences of the two enzymes. Their genes were found to be closely linked and are arranged in opposite orientations. Hybridization mapping and partial sequence analyses indicate that the gene of an additional peptide synthetase, most likely the gene of ACMS III (acmC), is located immediately downstream of acmB in the same orientation. The protein sequence of ACMS II, deduced fromacmB, shows that the enzyme contains two amino acid activation domains, which are characteristic of peptide synthetases, and an additional epimerization domain. Heterologous expression ofacmB from the mel promoter of plasmid PIJ702 inStreptomyces lividans yielded a functional 280-kDa peptide synthetase which activates threonine and valine as enzyme-bound thioesters. It also catalyzes the dipeptide formation of threonyl–l-valine, which is epimerized to threonyl–d-valine. Both of these dipeptides are enzyme bound as thioesters. This catalytic activity is identical to the in vitro activity of ACMS II from S. chrysomallus.
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Ma, Yan, Xiaoping Xu, Xiaoqin Wang, Bobin Chen, and Guowei Lin. "Atypical Chronic Myeloid Leukemia: An Analysis of 9 Cases." Blood 112, no. 11 (November 16, 2008): 4285. http://dx.doi.org/10.1182/blood.v112.11.4285.4285.
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Abstract Objective FTo investigate the clinical characteristics of atypical chronic myeloid leukemia (aCML) and characterize the aCML. Methods FFrom 2003 to 2007, the consecutive samples of 54 MDS/MPD patients in Sino-US Shanghai Leukemia Cooperative Group were collected by prospective methods and diagnosed with WHO classification. We identified 9 aCML cases and analyzed the clinical and laboratory data of these cases. Results FThe median age of 9 cases was 66 years old(range 38~78y). The ratio of male and female is 1:1.25. Median hemoglobin concentration was 76.5g/L(range 43.3~116), median white blood cell count 27.5×109/L(range 7.55 ~317.2), median neutrophil percentage 66.4%(range 43.3~83.5), median basophil percentage 2.86%(range 0.24~5.79), median monocyte percentage 7.59%(range 0.92~16.3), median platelet 77.6×109/L(range 20.7 ~504)and median marrow blast percentage 2.5 %(range 0.5~6). Abnormal karyotype occurred in 20% of all patients. Median survival was 11.5 months(2.5 `44months). Conclusions FaCML occurs rarely and is associated with a poor prognosis. The major distinguishing features of aCML are Ph(−)or BCR/ABL(−)and severe dysgranulopoiesis. In addition, hepatosplenomegaly and leukocytosis are less prominent in aCML than chronic myeloid leukemia(CML) and chronic myelomonocytic leukemia (CMML). Anemia is much severe than CML and CMML.
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Meggendorfer, Manja, Tamara Alpermann, Torsten Haferlach, Carina Schrauder, Rabea Konietschke, Claudia Haferlach, Wolfgang Kern, and Susanne Schnittger. "Mutational Screening Of CSF3R, ASXL1, SETBP1, and SRSF2 In Chronic Neutrophilic Leukemia (CNL), Atypical CML and CMML Cases." Blood 122, no. 21 (November 15, 2013): 105. http://dx.doi.org/10.1182/blood.v122.21.105.105.
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Abstract Introduction Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloproliferative and myelodysplastic/myeloproliferative neoplasms. So far, the diagnosis of CNL and aCML has been based on cytomorphology and the absence of JAK2V617F and PDGFR rearrangements. Recently, mutations in CSF3R and SETBP1 were identified and associated with CNL and aCML, respectively. Chronic myelomonocytic leukemia (CMML) and aCML also share several characteristics and need to be discriminated especially by the absolute number of monocytes in the peripheral blood. Aim To determine the frequency of CSF3R mutations (CSF3Rmut) in CNL, aCML, and CMML and to investigate a mutation pattern, cytogenetics and clinical data in all three entities. Patients and Methods To first delineate patients with potential CNL, we investigated blood and bone marrow smears and depicted patients with a white blood cell count >25x109/L, neutrophils >80%, immature granulocytes <10%, <1% myeloblasts and hypercellular bone marrow (according to WHO 2008). BCR-ABL1 fusion transcript, JAK2 and MPL mutations were excluded in all cases by RT-PCR and melting curve analyses. Indication for PDGFR rearrangements was precluded by over-expression analyses of PDGFRA and PDGFRB by quantitative real-time PCR, resulting in a final cohort of 20 cases declared as CNL patients. Additional 60 aCML and 252 CMML patients were included. Cytogenetics was available in 330/332 cases. Mutations in CSF3R exons 14 and 17 (n=332), in ASXL1 exon 13 (n=321), and the mutational hot spots in SETBP1 (n=331) and SRSF2 (n=320) were analyzed by Sanger sequencing. Results In the total cohort of 332 patients we detected CSF3R mutations in 11 cases (3.3%). 8/11 cases showed a p.Thr618Ile mutation in exon 14, four of them carried an additional nonsense/frame-shift mutation in exon 17. One additional patient was mutated in p.Thr615Ala and showed a nonsense mutation in exon 17. Two cases showed a mutation in exon 17 only, one a nonsense the other a frame-shift mutation, respectively. Analyzing the mutation frequencies within the different entities revealed a clustering of CSF3Rmut within CNL cases with 7 of 20 (35%) mutated cases in contrast to 2 of 60 (3.3%; p=0.001) aCML and 2 of 252 (0.8%; p<0.001) CMML cases. Cytogenetics in CSF3Rmut cases showed that 9/11 cases had a normal karyotype and only one aCML patient harbored a del(3q) and one CMML patient a complex karyotype. Mutations in the three other analyzed genes ASXL1, SETBP1 and SRSF2 were detected in the total cohort in 156/321 (49%), 34/331 (10%), and 149/330 (45%) patients, respectively. Analyses regarding concomitant mutations of CSF3R with ASXL1, SETBP1 or SRSF2 revealed no additional mutation in two cases. In 8 of 11 parallel analyzed CSF3Rmut patients an ASXL1mut was identified, SETBP1 as well as SRSF2 were mutated in 3 of the 11 cases. Notably, the 7 CSF3Rmut within the CNL group had no mutation in SETBP1. Analysis of mutational loads in CNL showed that 6/7 CSF3Rmut had a higher mutational load than the second mutated gene (range: 25-50% vs. 10-30%). In one case both mutated genes had equal mutational loads (40%). In contrast, in CMML and aCML 3/4 patients had lower mutational loads in CSF3Rmut than in the additional mutated genes (20-50% vs. 40-50%), while also one case showed equal mutational loads in the mutated genes (50%). Combining the mutational results of these four genes indicate a specific and individual molecular pattern for these three different entities. While ASXL1 is frequently mutated in all entities (CNL: 8/11 (73%); aCML: 38/59 (64%); CMML: 110/251 (44%)), SRSF2 shows the highest mutation frequency in CMML cases (121/251; 48%), followed by aCML (24/60; 40%) and CNL (4/19; 21%). In contrast, SETBP1 is often mutated in aCML (19/60; 32%) and rarely in CMML (13/252; 5%) and CNL (2/19; 10.5%) patients. In addition, CSF3R is much more associated with the CNL cases (35%) and less frequently found in aCML (2%) and CMML (1%). Conclusion 1) CNL, aCML and CMML are related diseases and difficult to distinguish by cytomorphology alone and therefore require additional diagnostic criteria, i.e. molecular mutations. 2) ASXL1 is the most frequently mutated gene in these entities and thus can help to prove clonality. 3) SETBP1 much more closely relates to aCML and SRSF2 to CMML. 4) Mutations in the novel marker CSF3R are closely related to CNL and thus qualify as a new molecular marker for diagnosis of CNL. Disclosures: Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schrauder:MLL Munich Leukemia Laboratory: Employment. Konietschke:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Gao, Tianqi, Changhui Yu, Si Xia, Ting Liang, Xuekui Gu, and Zenghui Liu. "A rare atypical chronic myeloid leukemia BCR-ABL1 negative with concomitant JAK2 V617F and SETBP1 mutations: a case report and literature review." Therapeutic Advances in Hematology 11 (January 2020): 204062072092710. http://dx.doi.org/10.1177/2040620720927105.
Full textAbstract:
Atypical chronic myeloid leukemia (aCML) BCR-ABL1 negative is a rare myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) for which no standard treatment currently exists. The advent of next-generation sequencing has allowed our understanding of the molecular pathogenesis of aCML to be expanded and has made it possible for clinicians to more accurately differentiate aCML from similar MDS/MPN overlap syndrome and MPN counterparts, as MPN-associated driver mutations in JAK2, CALR, or MPL are typically absent in aCML. A 55-year old male with main complaints of weight loss and fatigue for more than half a year and night sweats for more than 2 months was admitted to our hospital. Further examination revealed increased white blood cells, splenomegaly, and grade 1 bone marrow fibrosis with JAK2 V617F, which supported a preliminary diagnosis of pre-primary marrow fibrosis. However, in addition to JAK2 V617F (51.00%), next-generation sequencing also detected SETBP1 D868N (46.00%), ASXL1 G645fs (36.09%), and SRSF2 P95_R102del (33.56%) mutations. According to the 2016 World Health Organization diagnostic criteria, the patient was ultimately diagnosed with rare aCML with concomitant JAK2 V617F and SETBP1 mutations. The patient received targeted therapy of ruxolitinib for 5 months and subsequently an additional four courses of combined hypomethylating therapy. The patient exhibited an optimal response, with decreased spleen volume by approximately 35% after therapy and improved symptom scores after therapy. In diagnosing primary bone marrow fibrosis, attention should be paid to the identification of MDS/MPN. In addition to basic cell morphology, mutational analysis using next-generation sequencing plays an increasingly important role in the differential diagnosis. aCML with concomitant JAK2 V617F and SETBP1 mutations has been rarely reported, and targeted therapy for mutated JAK2 may benefit patients, especially those not suitable recipients of hematopoietic stem cell transplants.
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Donadoni, Carla, Rocco Piazza, Diletta Fontana, Andrea Parmiani, Alessandra Pirola, Sara Redaelli, Giovanni Signore, et al. "Evidence of ETNK1 Somatic Variants in Atypical Chronic Myeloid Leukemia." Blood 124, no. 21 (December 6, 2014): 2212. http://dx.doi.org/10.1182/blood.v124.21.2212.2212.
Full textAbstract:
Abstract Atypical Chronic Myeloid Leukemia (aCML) is a clonal disorder belonging to the Myeloproliferative/Myelodysplastic (MPN/MDS) group. The molecular lesions responsible for the onset of aCML remained unknown until 2013 when recurrent somatic mutations of SETBP1 were identified. However, the frequency of SETBP1 mutations in aCML does not exceed 25-30%, which suggests that other lesions may play a role in the remaining cases. To gain further insight into the somatic variants responsible for the onset of aCML, we generated whole-exome and transcriptome sequencing data on 15 matched case/control aCML samples. A total of 151 non-synonymous and 42 synonymous single-nucleotide somatic variants were identified. Of these, 140 were transitions and 53 transversions. Of the non-synonymous mutations, 141 were missense and 10 nonsense mutations. In 2/15 (13.3%) samples we identified the presence of missense, single-nucleotide somatic variants occurring in the ETNK1 gene affecting two contiguous residues: H243Y and N244S. Sanger sequencing confirmed the presence and the somatic nature of the variants. Targeted resequencing of 383 clonal hematological disorders showed evidence of mutated ETNK1 in 7/70 aCML (10.0%, 95% C.I. 4.6-19.5%) and in 2/77 chronic myelomonocytic leukemia samples (CMML; 2.6%, 95% C.I. 0.2-9.5%) %), while no ETNK1 mutations were identified in the remaining hematological disorders. All the variants were heterozygous and clustered in the same, highly conserved region within the kinase domain (1/9 H243Y and 8/9 N244S). Somatic, heterozygous ETNK1 variants have been also recently reported in 10% of Systemic Mastocytosis (SM) cases and in 22% of SM with associated hypereosinophilia (Lasho T et al., Abstract 4062, EHA2014); strikingly, there is a large overlap between the variants that we identified in aCML and CMML and those described for SM (3 N244S and 2 G245A), which suggests that the common hotspot region may play a critical and yet unknown functional role. The hitherto described data suggest that ETNK1 variants are restricted to a limited subset of hematological disorders. This is further supported by the lack of somatic ETNK1 mutations in 60 paired whole-genome and over 600 exomes, comprising 276 paired tumor/germline primary samples and 344 cancer cell lines (http://cancer.sanger.ac.uk/cancergenome/projects/cell_lines/). In 2/6 ETNK1 mutated aCML cases (33%, 95% C.I. 9%-70%), we detected the presence of a coexisting somatic SETBP1 variant. The fraction of SETBP1 mutations identified in this group is perfectly in line with the overall frequency of SETBP1 mutations in aCML, suggesting that mutations occurring in ETNK1 and SETBP1 are not mutually exclusive. To discriminate if ETNK1 and SETBP1 mutations occur in different or in the same clone, we performed colony assay experiments, revealing the coexistence of the two somatic mutations within the same clone. Liquid Chromatography – Mass Spectrometry experiments revealed that in ETNK1 mutated cells the intracellular levels of phosphoethanolamine are over 5-fold lower than in the wild-type counterpart (p < 0.05), suggesting that ETNK1 mutations may impair the physiological catalytic activity of the kinase. Taken globally these data identify ETNK1 somatic mutations as a new oncogenic lesion in aCML and CMML, two overlapping MDS/MPN neoplasms. They also show that ETNK1 variants apparently cause a loss-of-function effect, leading to a decrease in the intracellular levels of phosphoethanolamine. Disclosures Campbell: 14M Genomics Limited: Consultancy, Equity Ownership.
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Grand, Francis H., Claire E. Hidalgo-Curtis, Thomas Ernst, Katerina Zoi, Christine Zoi, Carolann McGuire, Sebastian Kreil, et al. "Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms." Blood 113, no. 24 (June 11, 2009): 6182–92. http://dx.doi.org/10.1182/blood-2008-12-194548.
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Abstract Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. To help identify novel mutations in myeloproliferative neoplasms (MPNs), we performed a genome-wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n = 30), JAK2 mutation–negative myelofibrosis (MF; n = 18), or JAK2 mutation–negative polycythemia vera (PV; n = 10). Stretches of homozygous, copy neutral SNP calls greater than 20Mb were seen in 10 (33%) aCML and 1 (6%) MF, but were absent in PV. In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 CBL variants in 26 patients with aCML, myelofibrosis or chronic myelomonocytic leukemia. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs.
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Ashangari, Chandralekha, and Praveen K. Tumula. "Atypical Chronic Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 5455. http://dx.doi.org/10.1182/blood-2018-99-110189.
Full textAbstract:
Abstract Introduction: Atypical chronic myeloid leukemia (aCML), BCR-ABL1 negative is a rare myelodysplastic syndromes (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. We present one of the rare presentations of aCML in an elderly patient. Case: A 76 year old male presented to the Hematology clinic for consultation after discharge from local hospital for elevated WBC count. Past medical history was significant for COPD, acid reflux, peripheral arterial disease and hypertension. Physical exam was unremarkable. Initial labs were significant for leukocytosis of 30 k/cu mm, anemia with Hb 10 gm/dl, thrombocytosis 695,000 with neutrophilia of ANC 25,200. Peripheral blood was negative for JAK2 V617F and BCR-ABL. Peripheral blood flow cytometry showed granulocytic left shift with 1.5% myeloblasts. Bone marrow biopsy suggestive of hypercellular marrow (100%) with myeloid predominance, atypical megakaryocytes, increased ring sideroblasts (49% of NRBC), increased blasts (5%) and dysgranulopoeisis over all suggestive of Myelodyplastic Syndrome/Chronic Myeloproliferative Disorder (MDS/MPD). Cytogenetics were positive for U2AF1 positive, CSF3R T6181, CSF3R Q776 pathognomonicof atypical CML and negative for BCR-ABL, FLT3. He was considered transplant ineligible. He was started on Azacitadine and is currently receiving 2nd cycle therapy. He is also receiving darbepoeitin periodically to avoid frequent transfusions. He is currently transfusion independent. Discussion: Increased WBC count (e.g., cutoffs of >40×109/L or 50×109/L), increased percentage of peripheral blood myeloid precursors, female sex, and older age are adverse prognostic factors for overall survival or leukemia-free survival in aCML. aCML cases lack in Philadelphia chromosome. Overall 50-65% of patients show cytogenetic abnormalities. The most frequent is +8 (25%). Other changes such as -7 and del(12p) have also been recurrently observed. Patients with aCML have an estimated median survival between 14 and 30 months. aCML tends to exhibit a more aggressive clinical course than other MDS/MPN subtypes. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Meggendorfer, Manja, Wencke Walter, Stephan Hutter, Wolfgang Kern, Claudia Haferlach, and Torsten Haferlach. "FOS Expression Distinguishes Two Groups of Atypical CML (aCML) Allowing Targeted Therapy." Blood 132, Supplement 1 (November 29, 2018): 3893. http://dx.doi.org/10.1182/blood-2018-99-111832.
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Abstract BCR-ABL1 negative myeloproliferative neoplasms not only include atypical chronic myeloid leukemia (aCML), but also chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), and myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN, U). Despite the recent advances in characterizing aCML more specifically, based on next generation sequencing data, the differential diagnosis and subsequent treatment decisions remain difficult. Therefore, we analyzed the transcriptome and performed whole genome sequencing (WGS) in a cohort of morphologically defined 231 patients (pts): 49 aCML, 30 CNL, 50 MDS/MPN, U, and 102 CMML all diagnosed according to WHO classification. WGS libraries were prepared with the TruSeq PCR free library prep kit and sequenced on a NovaSeq 6000 or HiSeqX instrument with 100x coverage (Illumina, San Diego, CA). The Illumina tumor/unmatched normal workflow was used for variant calling. To remove potential germline variants, each variant was queried against the gnomAD database, variants with global population frequencies >1% where excluded. For transcriptome analysis total RNA was sequenced on the NovaSeq 6000 with a median of 50 mio. reads per sample. The obtained estimated gene counts were normalized and the resulting log2 counts per million (CPMs) were used as a proxy of gene expression. Unsupervised exploratory analysis techniques, such as principal component analysis (PCA) and hierarchical clustering (HC) were used to identify groups of samples with similar expression profiles. We observed a high similarity between the different entities with CMML being the most distant entity, followed by CNL. MDS/MPN, U and aCML were the most similar entities. Due to high within-group heterogeneity, we found that it was impossible to identify a gene expression signature that separated aCMLs reliably from the other MDS/MPN overlap entities. Surprisingly, PCA as well as HC indicated the existence of two subgroups within the aCMLs. Therefore, we searched for genes with a bimodal-like expression profile. We found that FOS expression levels strongly separated aCMLs into two groups of 16 pts (FOSlow) and 33 pts (FOShi), respectively. Interestingly, FOShi correlated with mutations in SETBP1 (12/33, 36% vs. 3/16, 19%), a known marker typically mutated in aCML (Figure 1a). Addressing the mutational landscape of these two groups (FOShivs.FOSlow) we found that ASXL1 (88% vs. 100%), TET2 (33% vs. 50%), SRSF2 (45% vs. 56%), EZH2 (27% vs. 31%), and NRAS (21% vs. 25%) showed rather similar mutation frequencies. GATA2 (15% vs. 31%) and RUNX1 (18% vs. 38%) mutations were less frequent in FOShi, whereas SETBP1 and CBL (18% vs. 6%) were more frequent in this group. Consistent with known features of SETBP1 mutation this group showed a higher white blood cell count (78 x109/L vs. 52 x109/L) and platelet count (158x109/L vs. 90x109/L), although none of these differences were significant. The two groups were further analyzed for gene expression differences and we found 16 genes with synchronized upregulation within the FOShi group that were differentially expressed (FDR < 0.05, absolute logFC > 1.5) compared to FOSlow. Functional enrichment analysis linked those genes with regulation of cell proliferation (p<0.001), negative regulation of cell death (p<0.001), and the AP-1 complex (p<0.001). Those 16 genes included the transcription factors JUN, FOSB, EGR3, and KLF4, the cancer-related genes DUSP1, RHOB, OSM, TNFRSF10C, and CXCR2, and the FDA approved drug targets JUN, COX-2, and FCGR3B (Figure 1b). JUN/FOS are the main components of the AP-1 complex, a regulator of cell life and death. The upregulation of these genes results in increased proliferation as clinically observed in aCML pts. Furthermore, for these pts a treatment with INFα might result in an anti-proliferative effect by modulation of FOS transcript levels. Further, COX-2 inhibitors might also suppress proliferation and differentiation of leukemia cells. However, for the FOSlow pts these treatments might not be as effective due to the already low expression levels of the respective genes. Since the expression levels of FOShi equal those of MDS/MPN overlap, whereas FOSlow levels are closer to the ones of a healthy control cohort, SETBP1 mutation might be a marker and indicator for pts with high FOS expression and therefore providing further treatment options by targeting specifically the FOS mediated pathways. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Walter:MLL Munich Leukemia Laboratory: Employment. Hutter:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Dao, Kim-Hien T., Jason Gotlib, Michael M. N. Deininger, Stephen T. Oh, Jorge E. Cortes, Robert H. Collins, Elliot F. Winton, et al. "Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia." Journal of Clinical Oncology 38, no. 10 (April 1, 2020): 1006–18. http://dx.doi.org/10.1200/jco.19.00895.
Full textAbstract:
PURPOSE Colony-stimulating factor-3 receptor ( CSF3R)-T618I is a recurrent activating mutation in chronic neutrophilic leukemia (CNL) and to a lesser extent in atypical chronic myeloid leukemia (aCML) resulting in constitutive JAK-STAT signaling. We sought to evaluate safety and efficacy of the JAK1/2 inhibitor ruxolitinib in patients with CNL and aCML, irrespective of CSF3R mutation status. METHODS We conducted a phase II study of ruxolitinib in 44 patients (21 CNL and 23 aCML). The primary end point was overall hematologic response rate (ORR) by the end of 6 continuous 28-day cycles for the first 25 patients enrolled. We considered a response as either partial (PR) or complete response (CR). We expanded accrual to 44 patients to increase our ability to evaluate secondary end points, including grade ≥ 3 adverse events, spleen volume, symptom assessment, genetic correlates of response, and 2-year survival. RESULTS ORR was 32% for the first 25 enrolled patients (8 PR [7 CNL and 1 aCML]). In the larger cohort of 44 patients, 35% had a response (11 PR [9 CNL and 2 aCML] and 4 CR [CNL]), and 50% had oncogenic CSF3R mutations. The mean absolute allele burden reduction of CSF3R-T618I after 6 cycles was greatest in the CR group, compared with the PR and no response groups. The most common cause of death is due to disease progression. Grade ≥ 3 anemia and thrombocytopenia were observed in 34% and 14% of patients, respectively. No serious adverse events attributed to ruxolitinib were observed. CONCLUSION Ruxolitinib was well tolerated and demonstrated an estimated response rate of 32%. Patients with a diagnosis of CNL and/or harboring CSF3R-T618I were most likely to respond.
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Meggendorfer, Manja, Torsten Haferlach, Sabine Jeromin, Claudia Haferlach, Wolfgang Kern, and Susanne Schnittger. "Molecular Analyses of MDS/MPN Overlap Entities According to WHO Classification Reveal a Distinct Molecular Pattern for MDS/MPN, Unclassifiable." Blood 124, no. 21 (December 6, 2014): 4618. http://dx.doi.org/10.1182/blood.v124.21.4618.4618.
Full textAbstract:
Abstract Introduction: The World Health Organization (WHO) classification defines myelodysplastic/myeloproliferative neoplasms (MDS/MPN) based on clinical, morphologic, and laboratory findings that show features of MDS and characteristics more consistent with MPN. This category includes atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML), MDS/MPN, unclassifiable (MDS/MPN, U), and refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T). In recent years RARS-T, CMML, and also aCML were deciphered by several molecular studies, while MDS/MPN, U cases warrant closer investigations. Aim: To comprehensively investigate mutations in 17 genes known to be mutated in aCML, CMML, MDS/MPN, U, and RARS-T and to define entity specific mutation patterns in comparison to cytogenetic and clinical data. Patients and Methods: We investigated 179 patients diagnosed by cytomorphology, immunophenotyping and genetic studies following WHO criteria: 35 patients were diagnosed as aCML, 58 as CMML, 39 as MDS/MPN, U, and 47 as RARS-T. All patients underwent mutation analyses by a gene panel containing: ASXL1, TET2, DNMT3A, SRSF2, SF3B1, U2AF1, JAK2, CALR, MPL, NRAS, KRAS, CBL, BRAF, CSF3R, RUNX1, SETBP1, and NPM1. Gene mutations were analyzed by Sanger sequencing, next generation sequencing, melting curve analyses, or gene scan. Cytogenetics was available in 172/179 cases and was grouped as normal karyotype (n=128, 74%) or aberrant karyotype (n=44, 26%). Results: In the total cohort the most frequently mutated gene was ASXL1 (41%), followed by TET2 (40%), and the spliceosomal genes SF3B1 (31%) and SRSF2 (30%). Also frequently mutated were JAK2 (21%), NRAS (15%), RUNX1 (12%), and CBL (12%). All other investigated genes showed mutation frequencies below 10%. There were no significant differences between the 4 entities regarding frequencies of aberrant karyotypes (14-37%) and no correlation of the number of molecular mutations (0-6/patient) with any specific karyotype. Addressing the mutation patterns of these 4 entities showed that ASXL1 and TET2 are frequently mutated in all entities (19-60% and 26-53%, respectively), although significant differences between the entities exist (see figure): ASXL1 is less frequently mutated in RARS-T (19%) in comparison to aCML (60%; p<0.001) and CMML (52%; p=0.001), TET2 is more often mutated in CMML (53%) in comparison to MDS/MPN, U (26%; p=0.007) and RARS-T (32%; p=0.031). SRSF2 is more frequently mutated in CMML (53%) than in RARS-T (9%; p<0.001) and MDS/MPN, U (15%; p<0.001), SF3B1 is more often mutated in RARS-T (92%) than in all other entities (aCML: 11%, CMML: 5%, MDS/MPN, U: 13%; for all p<0.001). One important difference between aCML and CMML versus MDS/MPN, U and RARS-T was reflected by two different signaling pathways: i) JAK2/CALR/MPL (JAK/STAT pathway) were significantly more often affected in MDS/MPN, U (33%) and RARS-T (53%), (aCML: 9%, CMML: 7%; p<0.001). ii) NRAS/KRAS/CBL (RAS pathway) were more often mutated in aCML (37%) and CMML (52%), (MDS/MPN, U: 5%, RARS-T: 9%; p<0.001). The MDS/MPN, U cohort included most patients with no mutation in any analyzed gene (11/39, 28%) in contrast to aCML (2/23, 6%), CMML (5/58, 9%), and RARS-T (0/47, 0%). Furthermore all these MDS/MPN, U patients with no gene mutation had a normal karyotype. Looking at co-ocurrences of gene mutations in MDS/MPN, U revealed that SRSF2 and TET2 mutations occur together more frequently (4/10 vs. 2/29 in TET2wt; p=0.028). Of notice, in MDS/MPN, U U2AF1 (18%) was the most frequently mutated spliceosomal gene which was only rarely mutated in the other entities (5%, p=0.015). Conclusions: 1) ASXL1 and TET2 are the most frequently mutated genes found overall in MDS/MPN overlap. 2) SF3B1 mutations are specific for RARS-T. 3) SRSF2 is most frequently mutated in CMML, but also in aCML. 4) MDS/MPN, U is affected by mutations in all spliceosomal genes. 5) The JAK/STAT pathway is more often affected in MDS/MPN, U and RARS-T. 6) The RAS pathway is more often affected in aCML and CMML. 7) MDS/MPN, U shows a specific molecular pattern with characteristics reflecting a mixture of all other MDS/MPN entities. Red: gene mutation, orange: gene mutations combined, light grey: no mutation/normal karyotype, black: aberrant karyotype, white: not analyzed. Figure: Molecular abnormalities and cytogenetics in MDS/MPN entities. Figure:. Molecular abnormalities and cytogenetics in MDS/MPN entities. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Jeromin:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Braun, Thorsten, Aziza Debache, Hervé Roudot, Daniel Lusina, Sylvain Thépot, Virginie Eclache, Antoine Martin, et al. "Therapeutic Strategies in Patients with Atypical CML (aCML) and Unclassified MDS/MPN (MDS/MPN-U). a Single Center Report." Blood 124, no. 21 (December 6, 2014): 5610. http://dx.doi.org/10.1182/blood.v124.21.5610.5610.
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Abstract Introduction: The WHO defined overlapping MDS/MPN group includes two rare entities: BCR-ABL negative aCML and MDS/MPN-U, defined by at least 3 months persistent WBC >13G/l or platelets >450G/l with at least 1 cytopenia, significant dysplasia (>10%) in at least 1 lineage, no circulating monocytosis (<1G/l or less <10% WBC) and <20% peripheral and/or BM blasts (Wang et al. Blood 2014). aCML is distinguished from MDS/MPN-U by >10% immature circulating precursors. Median overall survival (OS) in aCML and MDS/MPN-U ranges from 12 to 22 months, without any standard treatment clearly defined. We previously found Azacitidine (AZA) to yield responses in BCR-ABL negative MPN including a small subset of MDS/MPN patients (Thépot el al. Blood 2011). Methods: 20 patients, with WHO defined aCML or MDS/MPN-U, were diagnosed in our center from November 2003 to January 2014. Their characteristics and response to treatments administered, including AZA (using IWG 2006 criteria for MDS and evolution of MPN characteristics, such as WBC and splenomegaly (SM) were analyzed. Results: Median age was 73.5 years (range 54-89), M/F 9/11, WHO diagnosis aCML (N=13) and MDS/MPN-U (N=7). Median WBC was 23.4G/l (13.2-96.4), median circulating myeloid precursors were 13.5% (4-66), median ANC was 13.1G/l (3.8-33.8), median Hb level was 10.6g/dl (7.2-14.5) and median platelets 125G/l (27-900). Median BM blast count was 3% (2-12). Five patients (25%) had SM at diagnosis (4 aCML; 1 MDS/MPN-U). Karyotype was normal in 9 and abnormal in 11: (isolated +8 (N=5), del20q (N=3), del5q (N=1), t(3 ;5);+8 (N=1) and tetrasomy 8 (N=1)). Of 14 patients analyzed, only 3 (21.4%) were JAK2-V617F mutated (2 aCML; 1 MDS/MPN-U). Median OS of the entire cohort was 26 months and median OS of aCML and MDS/MPN-U patients was 22 months and 32 months respectively (p=0.71). Time to disease progression (defined as the appearance of marrow blasts >5%, or of a new cytopenia (ANC<1.5G/l; Hb<10g/dl or transfusion dependency, Plt<100G/l) was 24 months. 11 patients (55%) progressed, including 4 to AML. At diagnosis, 8 patients received hydroxyurea (HU), 2 patients AZA because of transfusion dependent anemia and excess of blasts and 10 patients best supportive care only (BSC). At disease progression, 7/11 patients received AZA and 4 other therapies (intensive chemotherapy (IC), n=1, HU alone, n=1, BSC, n=2). HU yielded no significant ORR in the 9 patients treated except for control of WBC. The patient receiving IC had treatment failure. Six of the 9 patients treated with AZA also needed concomitant HU. Median BM blast count at AZA onset was 12% (5 aCML, 3 MDS/MPN-U, 1 AML) and median number of AZA cycles was 6 (3-11) with an ORR according to IWG 2006 criteria of 22.2% (2/9 patients) with 1 CR and 1 mCR+HI-P. In those 2 patients, WBC normalized despite HU discontinuation and a third patient experienced a significant decrease of SM while HU could be also discontinued. In this cohort of aCML and MDS/MPN-U, only 1/7 patients with chromosome 8 abnormalities responded to AZA. Median OS of patients receiving AZA was 12 months. All patients treated with AZA died from disease progression at the closing date of our study. Conclusions: Treatment options for aCML and MDS/MPN-U, other than supportive care and HU are currently mostly limited to investigational agents. The role, if any, of hypomethylating agents, in these diseases, is not established. In this single center cohort, 2 marrow responses (1 CR and 1 mCR+HI-P) with AZA were observed, yielding similar modest ORR as reported for proliferative CMML treated by AZA (Drummond et al. Leukemia 2014). Due to the rarity of these diseases, and their genetic heterogeneity, multicenter prospective trials are needed to assess any potential clinical benefit of hypomethylating agents. Disclosures No relevant conflicts of interest to declare.
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Kloos, Arnold, Felicitas Thol, Sabrina Klesse, Alessandro Liebich, Arne Trummer, Renate Schottmann, Rubén Trespando Jiménez, et al. "Patient Derived Xenotransplantation Model of Atypical Chronic Myeloid Leukemia (aCML)." Blood 126, no. 23 (December 3, 2015): 2836. http://dx.doi.org/10.1182/blood.v126.23.2836.2836.
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Abstract Background: Atypical chronic myeloid leukemia (aCML) is a rare disorder classified as one of the MPN/MDS overlap syndromes. aCML usually presents like CML but lacks the pathognomonic BCR-ABL fusion found in CML. Most patients progress to acute myeloid leukemia (AML) with a median time to AML of 11.2 months and have a median overall survival of only 12.4 months (Wang et al. Blood 2014). Recurrently mutated genes found in aCML patients include SETBP1 , CSF3R, NRAS, EZH2, ASXL1, ETNK1, and U2AF1. The pathogenesis of aCML is poorly understood and neither specific nor effective treatments besides hematopoietic stem cell transplantation are available. We therefore aimed at developing a patient derived xenotransplantation model that allows serial transplantation and expansion of human leukemic cells and evaluation of novel treatments and drugs in vivo. Patient and Methods: Bone marrow cells were harvested from a patient diagnosed with atypical CML based on persistent leukocytosis, immature circulating myeloid precursors (16% metamyelocytes, 8% myelocytes, 9% blasts), marked dysgranulopoiesis, minimal monocytosis and basophilia, hypercellular bone marrow with high myeloid/erythroid ratio and 6% myeloid blasts, dysplasia in megakaryocytes and erythroid progenitors, and absence of BCR-ABL and mutated JAK2. The patient had moderate anemia and normal platelet counts and cytogenetic analysis showed a normal karyotype. Eight hundred thousand bone marrow cells were injected intravenously in NOD/SCID IL-2 receptor γ (NSG) deficient mice. We monitored these mice for human cell engraftment by regular eye bleeds every 4 weeks. Bone marrow and spleen cells from engrafted mice were retransplanted in secondary and tertiary mice of the NSG strain transgenic for SCF, IL3 and GM-CSF (NSGS). Patient cells were analyzed for mutations in fifty four genes by next generation sequencing and mutations were confirmed by Sanger sequencing in primary patient cells and cells from tertiary mice. Results: Human CD45+ cells from the aCML patient showed increasing engraftment over time in the NSG mouse reaching 16% in peripheral blood and 35% in spleen at 26 weeks after transplantation. In secondary (n=2) and tertiary (n=4) mice we used NSGS recipient mice and observed considerably accelerated engraftment kinetics leading to 19, 21 and 73% human cells in peripheral blood, spleen and bone marrow, respectively, between 12 and 15 weeks after transplantation. The myeloid marker CD33 was expressed in 86% of human bone marrow cells, while lymphoid markers CD3 and CD19 were absent. The stem and progenitor phenotype CD34+CD38- was found in 11% of human cells. The progenitor marker CD123 was expressed in 42% of cells, while the myeloid marker CD14 was expressed in 6% of cells. Hemoglobin levels and platelet counts were considerably lower in secondary and tertiary recipients of aCML cells compared to control animals. Spleens were enlarged at time of sacrifice with an average spleen weight of 150 mg. Morphological evaluation of bone marrow cells in tertiary recipients revealed a characteristic picture for aCML with 39% neutrophils, 8% blasts and 53% myeloid progenitors and monocytes. Molecular analysis identified mutations in ASXL1, RUNX1 and EZH2 with variant allele frequencies of 49, 48 and 46 percent, respectively that were confirmed in human cells from tertiary recipient mice. Thus, we show that primary aCML cells can be expanded and serially transplanted in immunodeficient mice and suggest clonal stability of this model. Conclusion: We provide the first patient derived xenotransplantation model for atypical CML, which preserves the phenotypic and molecular characteristics of the primary disease and allows serial transplantation and expansion of aCML cells. This model will serve to better understand the pathogenesis of aCML and to test urgently needed novel treatment approaches. Disclosures No relevant conflicts of interest to declare.
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Gotlib, Jason. "How I treat atypical chronic myeloid leukemia." Blood 129, no. 7 (February 16, 2017): 838–45. http://dx.doi.org/10.1182/blood-2016-08-693630.
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Abstract Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. The challenges of aCML relate to its heterogeneous clinical and genetic features, high rate of transformation to acute myeloid leukemia, and historically poor survival. Therefore, allogeneic hematopoietic stem cell transplantation should always be an initial consideration for eligible patients with a suitable donor. Nontransplant approaches for treating aCML have otherwise largely relied on adopting treatment strategies used for MDS and MPN. However, such therapies, including hypomethylating agents, are based on a paucity of data. With an eye toward making a more meaningful impact on response rates and modification of the natural history of the disease, progress will rely on enrollment of patients into clinical trials and molecular profiling of individuals so that opportunities for targeted therapy can be exploited.
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Choi, Hyun-Woo, Hye-Ran Kim, Hwan-Young Kim, Ju-Heon Park, Jae-Sook Ahn, Duck Cho, Seung-Jung Kee, et al. "Prevalence and Clinical Impacts Of SETBP1 Mutation In East Asian Patients With MDS/MPN." Blood 122, no. 21 (November 15, 2013): 2629. http://dx.doi.org/10.1182/blood.v122.21.2629.2629.
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Abstract Introduction Recently, recurrent somatic SET-binding protein 1 (SETBP1) mutations were found in atypical chronic myeloid leukemia (aCML) and other related myeloid neoplasms. According to reports so far, SETBP1 mutations occur in 9% of myelodysplastic/myeloproliferative neoplasms (MDS/MPN), especially in high frequency (24∼30%) of aCML. SETBP1 mutations were associated with worse prognosis and higher white blood cell (WBC) counts. Most of the reports came from western countries and there was a need to further study its clinicopathological impacts in East Asian patients because of paucity of reports. Therefore, this study investigated the prevalence and clinical implications of SETBP1 mutations in MDS/MPN patients at a single medical center in South Korea. Patients and methods We analyzed a cohort of 34 MDS/MPN patients (10 aCML, 7 CMML-1, 9 CMML-2, 5 JMML, 3 MDS/MPN unclassifiable) who were diagnosed and treated in Chonnam National University Hwasun Hospital (Hwasun, Korea) from October 2004 to June 2013. The mononuclear cells from bone marrow of the patients were separated and the total DNA was extracted by commercial kit (QIAGEN, Hilden, Germany). PCR and sequencing reaction were performed by targeting the hot spot (exon 4, codon 778-979) of the SETBP1 gene. The PCR mixture consisted of 50 to 100 ng of total DNA, 20 pmol of each forward (5'-CCACTTTCAACACAGTTAGGTG-3') and reverse (5'-TCTCGTGGTAGAAGGTGTAACTC-3') primer, 0.4 mM of each dNTP, 5 μL 10X F-taq reaction buffer, 5 U of DNA Polymerase (Solgent, Daejeon, Korea) and H2O in a final reaction volume of 50 μL. Direct sequencing was performed using the ABI Prism 3130XL Genetic Analyzer with the BigDye Terminator v3.1 Ready Reaction Kit (Applied Biosystems). Clinical information about patients was obtained from our electronic medical record database. All statistical computations were performed using PASW 18.0 (SPSS Inc., Chicago, Illinois, USA). Results In this analysis, 4 (11.7%) of 34 MDS/MPN patients showed SETBP1 mutations. 3 of them were aCML patients and 1 was CMML-2 patient. The frequencies in aCML and CMML-2 were 30% and 11.1%, respectively. All of the aCML patients with SETBP1 mutation showed mutation encoding c.2898G>A (p.Asp868Asn) and the CMML-2 patient displayed c.2903C>T synonymous mutation (Ser869).The mutated SETBP1 patients showed a tendency of higher mean WBC counts, lower mean hemoglobin, lower mean platelet counts and lower mean BM blasts percentage than the wild-type patients, but they were not statistically significant. One of the mutated SETBP1 patients showed a i(17)(q10) cytogenetic abnormality. We found no statistical difference in overall survival (OS) between mutated SETBP1 patients and wild-type patients. Conclusions Alteration of SETBP1 gene was a common genetic event in aCML with an impact as a diagnostic marker for MDS/MPN. Disclosures: No relevant conflicts of interest to declare.
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Fontana, Diletta, Daniele Ramazzotti, Andrea Aroldi, Antonio Niro, Luca Massimino, Delphine Rea, Fabio Stagno, et al. "Integrated Genomic, Functional and Prognostic Characterization of Atypical Chronic Myeloid Leukemia (aCML) in a Cohort of 43 Patients." Blood 134, Supplement_1 (November 13, 2019): 1714. http://dx.doi.org/10.1182/blood-2019-126467.
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Atypical chronic myeloid leukemia (aCML) is a rare BCR-ABL1 negative clonal disorder, which belongs to the myelodysplastic/myeloproliferative group. This disease is characterized by recurrent somatic mutations in several genes including SETBP1, ASXL1 and ETNK1, as well as high genetic heterogeneity, thus posing a great therapeutic challenge. The clinical prognosis for aCML is poor, with a median overall survival of 18 months after diagnosis, and no established standards of care exist for its treatment. The dissection of the molecular processes underlying aCML leukemogenesis could therefore result decisive in ameliorating the prognosis for aCML. With the aim to provide a comprehensive genomic characterization of aCML and to link the detected alterations with the clinical course of the disease, we applied a high-throughput sequencing strategy to 43 aCML samples, including whole-exome sequencing and RNA sequencing. Our study confirms ASXL1 and SETBP1 as the most frequently mutated genes with a total of 43.2% and 30.2%, respectively; ETNK1 mutations are observed in 14% of patients. An average of 2 mutations per patient was observed [range: 0-5]. We characterized the clonal architecture in a subset of 8 aCML patients by means of colony assays and targeted resequencing. The results indicate that ETNK1 variants occur very early in the clonal evolution history of aCML, while SETBP1 mutations represent a late event; interestingly, in the two cases where ASXL1 was mutated together with SETBP1, its mutations occupied an intermediate hierarchical position. CBL mutations, when present, showed a tendency toward reaching homozygosity through somatic uniparental disomy. Stratification based on RNA-sequencing gene expression data (Ramazzotti, Daniele, et al. Nature communications 9.1 (2018): 4453) identified two clearly different populations (26 and 17 patients) in terms of Overall Survival (OS), with 2 year OS of 69.23% [95% IC: 48.21%-86.67%] and 35.29% [95% IC: 14.21%-61.67%] respectively (logrank test for trend: p=0.004, Fig. 1A). In addition, the group with better prognosis showed a higher frequency of ETNK1 mutations (hypergeometric test: p=0.032). We next performed differential gene expression analysis to detect genes differentially expressed between the two patients' populations. This analysis revealed 38 significant genes (t-test p-value adjusted for false discovery rate p<0.01) overexpressed in the group with negative outcome. Notably, the majority of these genes are known cancer drivers, such as IDH2, MEN1, MYC and TP53. Involved pathways include gene transcription and cell differentiation, mitochondrial activity and DNA repair. We then considered RNA-sequencing data for the 4 most significant genes within the previous list (namely DNPH1, GFI1B, PARP1 and POLRMT) to build a classifier capable of associating patients to the respective subtype (better vs. worse prognosis). Our results show that a random forest classifier (Ho, Tin Kam. Proceedings of 3rd international conference on document analysis and recognition. Vol. 1. IEEE, 1995) using the 4 most significant genes achieves a 93.79% accuracy assessed by means of 10 fold cross validation (Fig.1B-C). In conclusion, we present here the first description of a large aCML cohort, in which sequencing data, clonal hierarchy of mutations and gene expression profiles were integrated through bioinformatics analysis. RNA-sequencing data stratification characterizes two groups with different prognosis; a classifier based on the 4 top differently expressed genes accurately predicts patients' outcome. Figure 1. A) Overall Survival curve (Kaplan-Meier curve) at 24 months shows significant different outcomes (p=0.004). B) Random forest classifiers learn multiple decision trees in order to predict outcomes. In the figure, an example of decision tree where nodes are genes and leaves are outcomes (better/worse prognosis). C) Heatmap of expression fold change for the top four differentially expressed genes. Figure 1 Disclosures Rea: BMS: Honoraria; Incyte Biosciences: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stagno:Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Elli:Novartis: Membership on an entity's Board of Directors or advisory committees. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; Bristol-Meyers Squibb: Consultancy.
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Khanna, Vishesh, Christopher A. Eide, Cristina E. Tognon, Julia E. Maxson, Beth Wilmot, Daniel Bottomly, Shannon K. McWeeney, Brian J. Druker, and Jeffrey W. Tyner. "Recurrent Pathogenic Cyclin D2 Mutations in Myeloid Malignancies." Blood 128, no. 22 (December 2, 2016): 2734. http://dx.doi.org/10.1182/blood.v128.22.2734.2734.
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Abstract Introduction: Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare hematologic neoplasms characterized by leukocytosis, a hypercellular bone marrow with granulocytic predominance, absence of the Philadelphia chromosome (t(9;22); BCR-ABL1), and absence of PDGFRA/B or FGFR1 gene rearrangements. While oncogenic mutations in colony stimulating factor 3 receptor (CSF3R) are commonly reported in CNL and, to a lesser extent, in aCML, a significant percentage of aCML and CNL cases lack well-defined pathogenetic lesions. In this study, we utilized whole exome sequencing and a functional genomics approach to identify recurrent cyclin D2 (CCND2)mutations in aCML/CNL. Methods: To achieve a more complete understanding of the pathogenic variants underlying these leukemias, genomic DNA was isolated from peripheral blood or bone marrow aspirates from 116 patients with aCML/CNL. Whole exome sequencing was then performed, allowing for the identification of novel and potentially deleterious recurrent mutations. Variants in CCND2 were prioritized for validation based on proximity to functional targets in protein interaction network databases and subsequently confirmed via Sanger sequencing. CCND2 expression was assessed by immunoblotting and immunofluorescence in NIH-3T3 cells. Transforming potential of the CCND2 mutations was assessed by examining IL-3-independent growth of Ba/F3 cells and murine bone marrow colony formation assays. Sensitivity of these mutations to CDK4/6 inhibition was examined via a colorimetric viability assay (MTS) at 72 hours following drug treatment. Results: Out of 116 suspected cases of aCML/CNL, we identified 4 cases (3.4%) that harbored recurrent mutations in CCND2, the gene encoding the cell cycle regulator cyclin D2. The mutations occurred in two nucleotides in a conserved region of the C-terminal PEST degradation domain and encoded either a P281S or a P281L (3 P281S, 1 P281L) variant. These variant proteins exhibited resistance to both degradation and to export from the nucleus, effectively resulting in accumulation of cyclin D2 protein. In turn, this accumulation was associated with increased murine bone marrow colony formation and sensitivity to CDK4/6 inhibition. Subsequent whole exome sequencing of 239 AML samples revealed the presence of the same variants (CCND2 P281S and P281L) in 3 samples (1.3%), suggesting that these variants may occur across multiple subsets of myeloid malignancy. Conclusions: Our study provides evidence of recurrent deleterious CCND2 mutations in aCML/CNL and AML. These mutations may contribute to oncogenesis in myeloid malignancy and are therapeutically targetable through CDK4/6 inhibition. Disclosures Druker: Agios: Honoraria; Ambit BioSciences: Consultancy; ARIAD: Patents & Royalties, Research Funding; Array: Patents & Royalties; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Other: travel, accommodations, expenses ; BMS: Research Funding; CTI: Equity Ownership; Curis: Patents & Royalties; Cylene: Consultancy, Equity Ownership; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses ; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Pfizer: Patents & Royalties; Roche: Consultancy.
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Castellino, Alessia, Elisa Santambrogio, Davide Rapezzi, and Massimo Massaia. "Atypical Chronic Myeloid Leukemia: New Developments from Molecular Diagnosis to Treatment." Medicina 57, no. 10 (October 14, 2021): 1104. http://dx.doi.org/10.3390/medicina57101104.
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Atypical Chronic Myeloid Leukemia, BCR-ABL1 negative (aCML) is a rare hematological entity, included in the group of myelodysplastic (MDS)/myeloproliferative (MPN) overlap syndromes. It is characterized by an aggressive course, a high rate of acute myeloid leukemia (AML) transformation, and a dismal outcome. The clinical presentation includes splenomegaly and leukocytosis with neutrophilia and left-shifted granulocytosis accompanied by granulocytic dysplasia and sometimes multilineage dysplasia. In past years, the disease incidence was likely underestimated, as diagnosis was only based on morphological features. Recently, the improving knowledge in the molecular biology of MDS/MPN neoplasms has made it possible to distinguish aCML from other overlapping syndromes, basing on next generation sequencing. Among the most commonly mutated genes, several involve the Jak-STAT, MAPK, and ROCK signaling pathways, which could be actionable with targeted therapies that are already used in clinical practice, opening the way to tailored treatment in aCML. However, currently, there are few data available for small samples, and allogeneic transplant remains the only curative option for eligible patients.
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Niro, Antonio, Rocco Piazza, Gabriele Merati, Alessandra Pirola, Carla Donadoni, Diletta Fontana, Sara Redaelli, et al. "ETNK1 Is an Early Event and SETBP1 a Late Event in Atypical Chronic Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 3652. http://dx.doi.org/10.1182/blood.v126.23.3652.3652.
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Abstract Atypical Chronic Myeloid Leukemia (aCML) is a clonal disorder belonging to the myelodisplastic-myeloproliferative neoplasms, according to the WHO-2008 classification. From a clinical point of view it closely resembles the classical Chronic Myeloid Leukemia (CML), however it lacks the presence of the Philadelphia chromosome and of the BCR-ABL1 fusion gene. In recent works, we and others characterized the somatic lesions present in the aCML genome, mainly by using Next Generation Sequencing (NGS) technologies, demonstrating the presence of a large set of recurrent somatic mutations involving, among the others, SETBP1, ETNK1, ASXL1, EZH2, CBL, TET2, NRAS and U2AF1 genes. The identification of somatic variants occurring in a large number of genes clearly indicates that the genetic bases of aCML are very heterogeneous, in striking contrast with classical CML. This heterogeneity poses a great challenge to the dissection of the molecular steps required for aCML leukemogenesis. The hierarchical reconstruction of the different mutations occurring in a clonal disorder can have important biological, prognostic and therapeutic repercussions; therefore we started a project focused on the dissection of the aCML clonal evolution steps through the analysis of individual leukemic clones by methylcellulose assays in samples whose mutational status has been previously characterized by matched whole-exome sequencing. Patient CMLPh-019 was characterized by the presence of a complex mutational status, with somatic variants occurring in SETBP1, ETNK1, ASXL1 and CBL genes (Fig. 1a). Targeted resequencing analysis of individual clones revealed the presence of all the 4 variants in 44/60 (73.3%) clones; in 15/60 (25%) we detected the presence of mutated ETNK1, ASXL1 and CBL and wild-type (WT) SETBP1. Of these 15 clones, 33% carried heterozygous and 67% homozygous CBL mutations. In one clone (1.7%) we detected heterozygous ETNK1, homozygous CBL and WT sequences for ASXL1 and SETBP1, suggesting a strong selective pressure towards the acquisition of homozygous CBL mutations. Identification of homozygous CBL mutations in all the main clonal phases suggests that a significant positive selective pressure is associated with this event. Allelic imbalance analysis of CMLPh-019 exome using CEQer revealed that CBL homozygosity is caused by a somatic uniparental disomy event occurring in the telomeric region of the long arm of chromosome 11. Patient CMLPh-005 (Fig. 1b) was mutated in ASXL1, CBL and SETBP1. Targeted analysis done on 68 clones revealed a complex, branching evolution, with 63 clones carrying all the 3 variants. Of them, 47 (74.6%) had a heterozygous and 16 (25.4%) a homozygous CBL variant. Four clones (4.2%) carried ASXL1 and SETBP1 but not CBL mutations, while 1 clone was mutated in ASXL1 and CBL in absence of SETBP1 mutations, which suggests that CBL mutations occurred independently in two different subclones. Also in this case, allelic imbalance analysis of exome data revealed that CBL homozygosity was caused by a telomeric somatic uniparental disomy event. According to exome sequencing, patient CMLPh-003 carried SETBP1 mutation G870S and NRAS variant G12R. Clonal analysis confirmed the presence of SETBP1 G870S in all the clones analyzed, while heterozygous NRAS G12R mutation was detected in 67% (Fig. 1c). Notably in the remaining 33% another heterozygous NRAS variant, G12D, was detected. Retrospective reanalysis of exome data confirmed the presence of the newly identified variant, which had been previously filtered-out from exome data because of the low frequency. Patient CMLPh-013 was mutated in ASXL1, ETNK1, NRAS and SETBP1. Of the 39 clones analyzed, 34 (82.9%) showed the coexistence of ASXL1, ETNK1, NRAS and SETBP1, 4 were mutated in ASXL1, ETNK1 and NRAS and 1 in ETNK1 and NRAS, suggesting that ETNK1 and NRAS were early events, ASXL1 an intermediate one and SETBP1 a late variant (Fig. 1d). Taken globally, these data indicate that ETNK1 variants occur very early in the clonal evolution history of aCML, while ASXL1 represents an early/intermediate event and SETBP1 is often a late event. They also suggest that, in the context of aCML, there is a strong selective pressure towards the accumulation of homozygous CBL variants, as already shown in other leukemias. Figure 1. Clonal analysis of four aCML cases. The asterisks indicate hypothetical clones. Figure 1. Clonal analysis of four aCML cases. The asterisks indicate hypothetical clones. Disclosures Rea: Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria.
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Shuvaev, Vasily, Karina Krutikova, Svetlana Menshakova, Natalya Kalinova, Irina Martynkevich, Lyubov Polushkina, Elena Belyakova, Yury Krivolapov, and Sergei Voloshin. "Atypical Chronic Myeloid Leukemia Challenge in Russian Hematology Practice." Blood 132, Supplement 1 (November 29, 2018): 5483. http://dx.doi.org/10.1182/blood-2018-99-114885.
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Abstract Background. The Atypical Chronic Myeloid Leukemia (aCML) and Chronic Neutrophilic Leukemia (CNL) had put in separate sections of myeloid neoplasms classification but have common entity and bone marrow changes. aCML and CNL hard to differentiate from each other. The main differential criterion is the proportion of immature white blood cells in blood, but it is not strong due to its instability. The achievement of recent years is discovering of aCML and CNL molecular factors: mutations in SETBP1 and CSFR3R genes gave the basis for the diagnosis confirmation in part of patients but could not differentiate between two nosologies. In addition, the access to the "uncommon" molecular diagnostic is complicated in routine clinical practice. Aim. At the abstract we would like to report the first, as we known, diagnosis of aCNL in Russia, that had been confirmed by molecular markers and is treating with target therapy. Materials and methods. The patient, female 51-year old has presented severe fatigue, pain, weight loss and burden under the left costal margin since Sep-2017. Results. The initial assessment has revealed massive splenomegaly (200x130x248 mm) with high WBC (133.9x109/L with left shift: blasts 1%, promyelocytes 6%, myelocytes 14%, metamylocytes 16%, bands 14%, segments 45%, lymphocytes 2%, monocytes 0%), mild anemia (10.4 g/dL) and normal platelets (223x109/L). There was neutrophil hyperplasia without eosinophilia and basophilia in myelogram. Initial diagnosis of typical CML was made but cytogenetic was normal and BCR-ABL (p190, p210) was negative. Atypical CML was suspected by bone marrow histology that demonstrated hypercellularity, granulocytic hyperplasia and mild megakaryocytic atypia and only mild reticuline fibrosis (MF-1). There were no MPN-driver markers (JAK2, CALR, MPL) revealed. Initial therapy with Hydroxyurea 2 g/day was started in Nov-2017. The re-work-up (morphological, cytogenetic, FISH and molecular) has been done in federal referral center in Nov-2017 but no signs of typical CML or Ph-MPN was detected. Mutation in exon 12 of ASXL1 gene was revealed in Jan-2018. After initial cytoreduction at follow-up in Feb-2018 mild leukocytosis (10.0-25.0x109/L) with shift to myelocytes and splenomegaly (+3 cm) was noted, severe fatigue and night sweats were still presented. Given the molecular results the target therapy with Ruxolitinib 15 mg BID was started since Feb-2018. The Ruxolitinib has given results with rapid resolution of constitutional symptoms, weight gain and complete CBC normalization during first month of therapy. At 3 months of treatment follow-up bone marrow histology showed hypocellularity and myeloid swelling. The first assessment of CSF3R gene in Russia on May-2018 has revealed the T618I mutation. Thus, the final diagnosis of aCML has been made (revealed mutation more related to CNL but WBC profile is consistent to aCML). The patient is still receiving Ruxolitinib therapy with complete clinical and hematologic response up to date. The search of unrelated donor was started. Conclusions. Nowadays diagnosis of aCML or CNL need to be established on thorough complex investigation. There is a need to get a widespread consensus guideline of aCML and CNL diagnosis and management and reclassification of these diseases in one common group. Disclosures No relevant conflicts of interest to declare.
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Chen, Lihan, Victoria Savalei, and Mijke Rhemtulla. "Two-stage maximum likelihood approach for item-level missing data in regression." Behavior Research Methods 52, no. 6 (April 24, 2020): 2306–23. http://dx.doi.org/10.3758/s13428-020-01355-x.
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AbstractPsychologists use scales comprised of multiple items to measure underlying constructs. Missing data on such scales often occur at the item level, whereas the model of interest to the researcher is at the composite (scale score) level. Existing analytic approaches cannot easily accommodate item-level missing data when models involve composites. A very common practice in psychology is to average all available items to produce scale scores. This approach, referred to as available-case maximum likelihood (ACML), may produce biased parameter estimates. Another approach researchers use to deal with item-level missing data is scale-level full information maximum likelihood (SL-FIML), which treats the whole scale as missing if any item is missing. SL-FIML is inefficient and it may also exhibit bias. Multiple imputation (MI) produces the correct results using a simulation-based approach. We study a new analytic alternative for item-level missingness, called two-stage maximum likelihood (TSML; Savalei & Rhemtulla, Journal of Educational and Behavioral Statistics, 42(4), 405–431. 2017). The original work showed the method outperforming ACML and SL-FIML in structural equation models with parcels. The current simulation study examined the performance of ACML, SL-FIML, MI, and TSML in the context of univariate regression. We demonstrated performance issues encountered by ACML and SL-FIML when estimating regression coefficients, under both MCAR and MAR conditions. Aside from convergence issues with small sample sizes and high missingness, TSML performed similarly to MI in all conditions, showing negligible bias, high efficiency, and good coverage. This fast analytic approach is therefore recommended whenever it achieves convergence. R code and a Shiny app to perform TSML are provided.
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Wu, Wubin, Jingchao Wang, Tianyong Zhang, Shuang Jiang, Xiaoyuan Ma, Guanghui Zhang, Xia Zhang, Xingwei Chen, and Bin Li. "Controllable synthesis of Ag/AgCl@MIL-88A via in situ growth method for morphology-dependent photocatalytic performance." Journal of Materials Chemistry C 7, no. 18 (2019): 5451–60. http://dx.doi.org/10.1039/c9tc00398c.
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Wang, John S., Omar Elghawy, Brett R. Kurpiel, and Michael G. Douvas. "Diagnosis and Management of Atypical Chronic Myeloid Leukemia with a t(2;13)(q33;q12) Translocation." Case Reports in Hematology 2022 (May 4, 2022): 1–5. http://dx.doi.org/10.1155/2022/4628183.
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Atypical chronic myeloid leukemia (aCML) is a rare myeloproliferative disorder that shares clinical features with chronic myeloid leukemia but lacks the classic t(9;22) BCR-ABL1 translocation and features prominent dysgranulopoiesis and granulocytic dysplasia. Challenges of this diagnosis include clinical and biologic heterogeneity, the high risk of transformation to acute myeloid leukemia, and the lack of standard treatment options. Allogeneic hematopoietic stem cell transplant is likely the preferred treatment, but this can be limited by patient psychosocial support, age, concomitant medical conditions, and availability of an appropriate donor. We report the case of a 61-year-old male with no significant past medical history diagnosed with aCML with a rare t(2;13)(q33;q12). He presented with weight loss, night sweats, splenomegaly, hyperleukocytosis, a leukoerythroblastic differential with a predominant neutrophilia, anemia, and thrombocytopenia. Subsequent peripheral blood and bone marrow studies lead to the diagnosis of aCML. He was recommended to undergo an allogeneic stem cell transplant evaluation and declined. He was initially treated with hydroxyurea and imatinib to which he responded for approximately three years. After clinical progression, he was treated with sorafenib, a multiprotein kinase inhibitor more commonly used in the treatment of hepatocellular and renal cell carcinoma due to its off target FLT3 inhibition. The patient achieved complete hematologic response which has been sustained for 7 years with tolerable side effects.
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Morita, Junya. "Research work in the Applied Cognitive Modelling Lab." Impact 2020, no. 7 (November 30, 2020): 9–11. http://dx.doi.org/10.21820/23987073.2020.7.9.
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Dr Junya Morita is based at the Applied Cognitive Modelling Laboratory (ACML) within the Department of Behavior Informatics at Shizuoka University in Japan. His team is conducting investigations that use computational models in an effort to improve our understanding of human minds and their inner workings. There are currently two directions of study underway at ACML. The first is concerned with theoretical studies of cognitive modelling, where the team try to construct models that explain human minds as computational and algorithmic levels. The second direction of study is the application of computational cognitive models. Morita and his team believe that there are fundamental values within the basic endeavours of cognitive science and are working to prove these values exist and are valid. Current topics of application include education, driving, entertainment, graphic design, language development, web navigation and mental illness.
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Piazza, Rocco, Simona Valletta, Alessandra Pirola, Hima Raman, Roberta Spinelli, Nick C. P. Cross, Caterina Cecchetti, Zaira Sortino, and Carlo Gambacorti-Passerini. "Whole-Exome Sequencing of 8 Atypical Chronic Myeloid Leukaemia Patients,." Blood 118, no. 21 (November 18, 2011): 3853. http://dx.doi.org/10.1182/blood.v118.21.3853.3853.
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Abstract Abstract 3853 INTRODUCTION According to the WHO-2008 classification, atypical chronic myeloid leukemia (aCML) is a myelodysplastic/myeloproliferative disorder clinically resembling the Philadelphia positive CML but lacking the BCR-ABL fusion. In aCML, the molecular lesions underlying the onset of the disease are unknown. To investigate the somatic events occurring in the genome of the aCML leukemic cells, we carried out whole-exome high-throughput sequencing analyses of 8 aCML patients. The results are described here. METHODS Peripheral blood (PB) or bone marrow cells were obtained after informed consent at diagnosis, before any therapy. Myeloid cells, evaluated by FACS, constituted more than 80% of total cells. Lymphocytes were obtained from PB samples, after culture with PHA/IL2 for 2–3 weeks. The exon-capture protocol was performed on myeloid leukemic cells and normal lymphocytes from the same patients using the Illumina TruSeq Exome Enrichment Kit. The enriched DNA was sequenced with a Genome Analyzer IIx (Illumina), using a 60 bases paired-end protocol and the TruSeq chemistry. On average, 10.5 Gigabases per exome were generated. The bioinformatic analysis was performed using the Galaxy framework (http://main.g2.bx.psu.edu/); the cross-match between leukemic and normal exomes was performed with dedicated in-house C# software. RESULTS The percentage of reads matching the reference human genome was over 90%, with a mean exon coverage of >70-fold and a percentage of exons with a mean coverage ≥ 20x of > 90% for both the leukemic sample and the control. The percentage of nucleotides targeting exonic regions or exonic regions plus 100bp was 48% and 68%, respectively, with an overall 28-fold enrichment for exonic vs. non-exonic regions. The comparison between the leukemic and the control datasets led to the identification of 63 single nucleotide somatic mutations with a relative mutation coverage of > 35%, corresponding to their heterozygous presence in >88% of cells. In total, 46 mutations were transitions and 17 transversions (transition/transversion ratio of 2.7), with the C:G->T:A event occurring at highest frequency (35/63; 55.6%). In 19/35 (54.3%) of the cases, the C:G->T:A transition occurred in the context of a CpG site. Among the 63 variants, 32.8% ranked more than 1.0 and 21.3% more than 2.0 in the GeneRanker cancer scoring system (http://cbio.mskcc.org/tcga-generanker/). Characterization of the top scoring biological functions (Ingenuity Pathway Analysis software) revealed a strong association with the core functional concepts of ‘Cancer/Leukaemia' (p = 3.74 * 10−6) and ‘Myeloproliferative disorder' (p = 9.91 * 10−6), with a total of 23 genes in the Cancer and 18 in the Leukaemia functional annotation. The top scoring cellular functions were connected with the core concepts of ‘Cellular growth and proliferation' (p = 1.03 * 10−3; 17 genes) and ‘DNA replication, recombination and repair' (5 genes). The latter comprised the functional annotations: ‘Chromatin formation', ‘Chromatin remodelling' and ‘Formation of chromosome components' (p = 6.76 * 10−3, 1.96 * 10−2 and 7.76 * 10−4, respectively). A Markov Cluster Algorithm analysis (String, http://string-db.org), confirmed the presence of the same two main mutational clusters (Fig. 1a,b). The individual mutations identified will be presented at the meeting, including two recurrent mutations. Taken globally, these data suggest that somatic mutations targeting a specific cellular proliferation pathway and a chromatin remodelling protein network (Fig. 1a,b) may play a critical role in the onset/clonal evolution of aCML. This information may prove useful in the next future in order to develop evidence-based aCML treatment protocols. Disclosures: No relevant conflicts of interest to declare.
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Tyner, Jeffrey W., Christopher A. Eide, Eric P. Stoffregen, Marc Loriaux, Stephanie G. Willis, Norbert Gattermann, Tibor Kovacsovics, Brian J. Druker, and Michael W. Deininger. "Identification of Tyrosine Kinase Mutations by Large-Scale DNA Sequencing in Patients with Chronic Myelomonocytic Leukemia/Atypical Chronic Myeloid Leukemia." Blood 108, no. 11 (November 16, 2006): 3606. http://dx.doi.org/10.1182/blood.v108.11.3606.3606.
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Abstract Chronic myeloid leukemia (CML) is caused by Bcr-Abl, a constitutively active tyrosine kinase. Chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML) both represent diseases with clinical features resembling CML, suggesting that their pathogenesis may be similar. Consistent with this, activating mutations of the platelet-derived growth factor receptor (PDGFR) and other tyrosine kinases are found in isolated patients, but the pathogenesis remains unclear in the majority. Elucidation of mechanistically important targets in the pathogenesis of CMML/aCML would allow for the design of targeted therapies for these disorders, perhaps repeating the success of imatinib in CML. To that end, we undertook a large-scale DNA sequencing screen aimed at identifying clinically important mutations in CMML. Methods: We assessed the genotypic status of 298 exons comprising the activation loop, juxtamembrane domain, and pseudokinase domain (where applicable) of all members of the tyrosine kinase family as well as exon 2 of the small GTPase, K-RAS. Ninety-six percent of exons were successfully amplified and sequenced in a 32-patient cohort with CMML/aCML. Sequence data was analyzed in comparison to wild type, and all mutations were screened against the database of human single-nucleotide polymorphisms (SNPs) for elimination of previously determined, clinically non-relevant sequence variations. Non-annotated amino acid exchanges were counterchecked by sequencing the respective exons in 96 healthy controls. Results: DNA sequence analysis of patients with CMML revealed that 19% of patients harbored the K-RASG13D mutation previously reported in acute myelogenous leukemia (AML) and CMML/aCML. In addition, 9% of patients harbored the JAK2V617F mutation that has been implicated in various myeloproliferative disorders. However, no other previously described, activating mutation was found in this DNA sequence screen. Notably, activating mutations in FLT3 and c-KIT, as detected in AML patients, were not found. We did, however, identify 73 different sequence variations. After exclusion of published SNPs and silent mutations, we identified thirty-one novel amino acid-changing mutations in 27 different exons. Thus far, comparison with normal controls has been completed for 20 exons and is ongoing in the remainder. Ten potential mutations were identified as previously undescribed SNPs, while 17 may represent true mutations. These include the tyrosine kinases FRK, FLT4, and EPHA8 among others. Studies are ongoing to determine the functional relevance of these novel mutations. Conclusions: Less than one-third of patients with CMML have previously described, activating tyrosine kinase or K-RAS mutations. Hence, as many as 70% of patients suffer from disease of unknown molecular origin. DNA sequence analysis has revealed several candidate mutations that may, upon further investigation, lead to molecular targets for therapeutic intervention in patients with CMML/aCML.
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Di Savino, Augusta, Cristina Panuzzo, Stefania Rocca, Ubaldo Familiari, Rocco Piazza, Sabrina Crivellaro, Giovanna Carrà, et al. "Morgana acts as an oncosuppressor in chronic myeloid leukemia." Blood 125, no. 14 (April 2, 2015): 2245–53. http://dx.doi.org/10.1182/blood-2014-05-575001.
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Key Points Morgana haploinsufficiency in mice causes a lethal and transplantable CML-like myeloid neoplasm. Morgana is underexpressed in aCML and in a subgroup of CMLs, where it predicts a worse response to imatinib but sensitivity to ROCK inhibitors.
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Wang, Sa A., Robert P. Hasserjian, Patricia S. Fox, Heesun J. Rogers, Julia T. Geyer, Devon Chabot-Richards, Elizabeth Weinzierl, et al. "Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms." Blood 123, no. 17 (April 24, 2014): 2645–51. http://dx.doi.org/10.1182/blood-2014-02-553800.
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Key Points Within MDS/MPN, the WHO 2008 criteria for aCML identify a subgroup of patients with aggressive clinical features distinct from MDS/MPN-U. The MDS/MPN-U category is heterogeneous, and patient risk can be further stratified by a number of clinicopathological parameters.
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Leung, Chi Sing. "Special issue on ACML 2015." Neurocomputing 258 (October 2017): 1–2. http://dx.doi.org/10.1016/j.neucom.2017.02.076.
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Abdul-Rahman, Shuzlina, Mohamad Soffi Abd Razak, Aliya Hasanah Binti Mohd Mushin, Raseeda Hamzah, Nordin Abu Bakar, and Zalilah Abd Aziz. "Simulation of simultaneous localization and mapping using 3D point cloud data." Indonesian Journal of Electrical Engineering and Computer Science 16, no. 2 (November 1, 2019): 941. http://dx.doi.org/10.11591/ijeecs.v16.i2.pp941-949.
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<span>Abstract—This paper presents a simulation study of Simultaneous Localization and Mapping (SLAM) using 3D point cloud data from Light Detection and Ranging (LiDAR) technology. Methods like simulation is useful to simplify the process of learning algorithms particularly when collecting and annotating large volumes of real data is impractical and expensive. In this study, a map of a given environment was constructed in Robotic Operating System platform with Gazebo Simulator. The paper begins by presenting the most currently popular algorithm that are widely used in SLAM namely Extended Kalman Filter, Graph SLAM and Fast SLAM. The study performed the simulations by using standard SLAM with Turtlebot and Husky robots. Husky robot was further compared with ACML algorithm. The results showed that Hector SLAM could reach the goal faster than ACML algorithm in a pre-defined map. Further studies in this field with other SLAM algorithms would certainly beneficial to many parties due to the demands of robotic application.</span>
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Nor, N. S. M., Mohamad Deraman, N. H. Basri, B. N. M. Dollah, Ramli Omar, Sepideh Soltaninejad, Rusli Daik, and M. D. Norizam. "Supercapacitor Activated Carbon Electrode from Composite of Green Monoliths of KOH-Treated Pre-Carbonized Oil Palm Empty Fruit Bunches and HNO3-Treated Graphite." Advanced Materials Research 1112 (July 2015): 303–7. http://dx.doi.org/10.4028/www.scientific.net/amr.1112.303.
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Supercapacitor electrodes in the form of activated carbon monoliths (ACMs) were prepared by carbonization and activation of three different composite of green monoliths (GMs) consisting of (a) self-adhesive carbon grains (SACG) derived from pre-carbonized oil palm empty fruit bunches, KOH and graphite additive, (b) KOH-treated SACG and HNO3-treated graphite additive, and (c) SACG and HNO3-treated graphite additive. The ACM1, ACM2 and ACM3 electrodes produced from their respective GMs were characterized using nitrogen adsorption-desorption technique and the supercapacitor cell fabricated using these electrodes were characterized by galvanostatic charge discharge method. The results showed that the change in the condition of material component in the GMs by acid/alkaline treatment moderately changed the pore characteristics of the electrodes, for example only around 10 % change occurred in the specific surface area of the samples. However, such change gave a larger change in the electrochemical performance of the cells, where the ACM3 exhibit the specific capacitance (119 F g-1) and specific energy (3.5 W h kg-1), which were (66 – 71) % and (28 – 75) % higher than the other cells, and the specific power (63.3 W kg-1), which was 33 % lower than the other cells. These results demonstrate a non-linear dependency of electrochemical performances of the cells on the porosity characteristics of the electrodes resulted from the modification of component materials in the GMs.
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Coltro, Giacomo, Guadalupe Belen Antelo, Terra Lasho, Christy Finke, Animesh Pardanani, Naseema Gangat, Ryan M. Carr, et al. "Phenotypic Correlates and Prognostic Outcomes of TET2 Mutations in Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Syndromes: A Comprehensive Study of 504 Patients." Blood 134, Supplement_1 (November 13, 2019): 3005. http://dx.doi.org/10.1182/blood-2019-124115.
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Introduction: Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes consist of 5 distinct WHO-defined entities; namely chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia, BCR/ABL1- (aCML), juvenile myelomonocytic leukemia (JMML), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), and MDS/MPN, unclassifiable (MDS/MPN-U) (Arber et al., Blood 2016). With the notable exception of JMML, a bona fide RASopathy, the other entities are characterized by clinical heterogeneity and molecular diversity. Loss of function TET2 mutations (TET2MT) are common in myeloid neoplasms, especially CMML (60%), and are known leukemogenic drivers. We carried out this study to assess the TET2 mutational landscape and phenotypic correlates in patients with MDS/MPN overlap syndromes. Methods: After approval by the institutional review board, adult patients with WHO defined MDS/MPN overlap syndromes were included; with the exception of JMML. The BM morphology, cytogenetics and 2016, WHO-diagnoses were retrospectively reviewed and all patients underwent targeted next generation sequencing for 29 myeloid-relevant genes, obtained on BM mononuclear cells, at diagnosis, or at first referral, by previously described methods (Patnaik et al., BCJ 2016). Results: Five hundred and four patients were included in the study; including 387 (77%) with CMML, 48 (10%) with MDS/MPN-RS-T, 17 (3%) with aCML and 52 (10%) with MDS/MPN-U. The median age at diagnosis was 71 (range, 18-99) years, and 333 (66%) were male. TET2MT were seen in 212 (42%) patients, with the frequency of other mutations being: ASXL1 45%, SRSF2 40%, NRAS 15%, SF3B1 13%, CBL, RUNX1 and SETBP1 12% each, and JAK2 V617F 11% (Figure B). Among the MDS/MPN overlap syndromes, TET2 was more frequently mutated in CMML (49%) and aCML (47%) compared to MDS/MPN-RS-T (10%) and MDS/MPN-U (15%). The prevalence of patients with TET2MT increased with age, a finding consistent across all MDS/MPN subtypes (Figure C). Overall, 341 TET2MT were identified in 212 patients (mean 1.6 variants/patient, range 0-5): 120 (24%) had >1 TET2MT, while 113 (22%), 5 (1%) and 2 (0.4%) had 2, 3 and 5 mutations, respectively. CMML and aCML patients were more likely to have an age-independent increase in multiple TET2MT (28% and 24%), in comparison to MDS/MPN-RS-T (4%) and MDS/MPN-U (8%). TET2 MT spanned the entire coding sequence and were mostly truncating (78%, Figure A): 59 (17%) were missense, 14 (4%) involved the splice-donor/acceptor sites, 2 (0.5%) were in-frame deletions, 129 (38%) were nonsense, and 137 (40%) were frameshift mutations. Overall, the distribution of TET2MT was superimposable across CMML, aCML, and MDS/MPN-U; the only exception being the absence of splice site mutations in the latter two. One hundred and eighty-seven (55%) TET2MT were secondary to pathogenic single nucleotide variants (SNV), while the remainders were secondary to deletions (25%) and insertions (15%). Transitions comprised the most frequent type of SNV (65%), with the C:G>T:A being the most common (56%). Patients with MDS/MPN overlap syndrome and TET2MT were more likely to have additional gene mutations compared to wild type patients (mean mutation number 3.1 vs 2.1, p<0.0001), with common co-mutations being SRSF2 (51%), ASXL1 (42%), and CBL (17%). The median overall survival (OS) of the entire cohort was 29 (range, 0-170) months; 29 months for CMML, 63 months for MDS/MPN-RS-T, 14 months for aCML, and 25 months for MDS/MPN-U. On univariate analysis, OS was superior in CMML patients with TET2MT (35 months) compared to wild type cases (21 months, p<0.0001, Figure D), and in CMML patients with >1 TET2MT (41 months) in comparison to wild type (21 months, p<0.0001) and single TET2MT (29 months, p=0.0476) cases (Figure E). These observations were not seen in patients with aCML, MDS/MPN-RS-T, and MDS/MPN-U. Conclusion: Our study demonstrates that TET2MT are among the most frequent mutations in patients with MDS/MPN overlap syndromes (42%), especially CMML (49%), with an age-dependent increase in the frequency and number of TET2MT. Mutations in TET2 were found to span the entire coding sequence, with truncating mutations being more common (78%). Importantly, in CMML, TET2MT, including number of TET2MT, were associated with favorable survival outcomes. Figure Disclosures Al-Kali: Astex Pharmaceuticals, Inc.: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.
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Kesarwani, Meenu, Zachary Kincaid, and Mohammad Azam. "MEK/ERK addiction in CNL/aCML." Oncotarget 8, no. 59 (November 3, 2017): 99215–16. http://dx.doi.org/10.18632/oncotarget.22283.
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Zhang, Peng, Xichuan Liu, Zhaoming Li, Zeming Zhou, Kun Song, and Pinglv Yang. "Attenuation Correction of Weather Radar Reflectivity with Arbitrary Oriented Microwave Link." Advances in Meteorology 2017 (2017): 1–17. http://dx.doi.org/10.1155/2017/6124149.
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To compensate radar reflectivity for attenuation effect, a new method for attenuation correction of the radar reflectivity using arbitrary oriented microwave link (referred henceforth to as ACML) is developed and evaluated. Referring to the measurement of arbitrary oriented microwave link, the ACML method optimizes the ratio of specific attenuation to specific differential phase which is a key parameter in attenuation correction schemes. The proposed method was evaluated using real data of a dual-polarization X-band radar and measurements of two microwave links during two rainstorm events. The results showed that the variation range of the optimized ratio was overall consistent with the results of the previous studies. After attenuation correction with the optimal ratios, the radar reflectivity was significantly compensated, especially at long distances. The corrected reflectivity was more intense than the reflectivity corrected by the “self-consistent” (SC) method and closer to the reflectivity of a nearby S-band radar. The effectiveness of the method was also verified by comparing the rain rates estimated by the X-band radar with those derived by rain gauges. It is demonstrated that arbitrary oriented microwave link can be adopted to optimize the attenuation correction of radar reflectivity.
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Jamieson, Catriona H. M., Jason Gotlib, Mark Chao, M. Rajan Mariappan, Marla LayRaj, Carol Jones, James Zehnder, et al. "Molecular Progenitor Profiling in Human Myeloproliferative Disorders." Blood 106, no. 11 (November 16, 2005): 118. http://dx.doi.org/10.1182/blood.v106.11.118.118.
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Abstract Myeloproliferative disorders (MPD) are clonal hematopoietic disorders characterized by a hypercellular marrow, an overabundance of distinct lineages of terminally differentiated progeny and a propensity to transform to acute myelogenous leukemia (AML). Recent reports revealed that a specific (V617F) mutation in JAK2 resulted in constitutive cytokine signaling and increased sensitivity to cytokines in a large proportion of patients with MPD. However, the stage of hematopoiesis at which this mutation occurs and whether additional mutations contribute to the evolution of MPD into AML has yet to be determined. We performed phenotypic and functional analyses of hematopoeitic stem cells (HSC), common myeloid progenitors (CMP), granulocyte-macrophage progenitors (GMP) and megakaryocyte-erythroid progenitors (MEP) in 63 MPD peripheral blood or bone marrow samples donated by patients with PV (n=15), essential thrombocythemia (ET; n=8), post-polycythemic myeloid metaplasia/myelofibrosis (PPMM/MF; n=5), chronic myelogenous leukemia (CML; n=7), atypical CML/myeloproliferative disease unspecified (aCML/UMPD; n=2), chronic eosinophilic leukemia (CEL; n=1), chronic myelomonocytic leukemia (CMML; n=13) and AML (n=12) in order to identify the stage of hematopoiesis at which mutations arose as well as to provide prognostic information on patients with a propensity to transform to AML. Of the MPD mononuclear cells sequenced, 12 of 15 PV, 2 of 5 ET, 3 of 3 post-polycythemic myeloid metaplasia, and 2 of 2 aCML samples were positive for the JAK2 V617F mutation. With regard to phenotypic changes in progenitor profiles, PV samples had an increase in CMP together with a distinctive IL-3Ra high population that distinguished it from all other MPD. Conversely, aCML, AML and proliferative CMML had a preponderance of GMP. Functional changes in progenitors were assessed using hematopoietic progenitor assays (Figure 1A and B). This methodology demonstrated that the differentiation potential of PV was already skewed toward the erythroid lineage at the HSC level in contrast to CMML, CML, aCML and AML HSC which produced a preponderance of myeloid colonies. In addition, the aberrant erythroid potential of PV HSC could be potently inhibited with a specific JAK2 inhibitor - AG490 suggesting that JAK2 plays a role in enhancing the erythroid differentiation potential of PV at the stem cell level. Finally, other molecular abnormalities were detected at the progenitor level in MPD including changes in GATA-1 and PU.1 expression, bcl-2 overexpression and beta-catenin activation that were associated with progression to AML. Thus, molecular progenitor profiling may provide prognostic information in a variety of MPD and could be a useful adjunct to current diagnostic methods. NBM versus MPD Colonies NBM versus MPD Colonies Normal BM vs PV Progenitor Colonies Normal BM vs PV Progenitor Colonies
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Grand, Francis, Claire Hidalgo-Curtis, Thomas Ernst, Katerina Zoi, Christine Zoi, Carolann McGuire, Sebastian Kreil, et al. "Frequent CBL Mutations Associated with 11q Acquired Uniparental Disomy in Myeloproliferative Neoplasms." Blood 112, no. 11 (November 16, 2008): 174. http://dx.doi.org/10.1182/blood.v112.11.174.174.
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Abstract Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. As a route towards identifying novel mutations in myeloproliferative neoplasms (MPN), we performed a genome wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n=30), JAK2 mutation negative myelofibrosis (MF; n=18) or JAK2 mutation negative polycythaemia vera (PV; n=10). Stretches of homozygous, copy neutral SNP calls >20Mb were seen in 10 (33%) aCML, 1 (6%) MF but absent in PV. In total seven different chromosomes were involved with 7q and 11q each affected in 3 (10%) of aCML cases and 1p, 13, 17q, 20q, 21q involved in single individuals. The 1p and 13 abnormalities were associated with homozygous mutations in MPL and FLT3, respectively. To characterize the two recurrent regions at 7q and 11q, we focused on genes encoding intracellular signal transduction components because of the known association between MPNs and deregulated tyrosine kinase signaling. No mutations were detected in MET, EPHA1, EPHB6 or BRAF but homozygous CBL missense mutations were found in all three cases with 11q aUPD. To determine the prevalence of CBL mutations, we sequenced exons 8 and 9 in an additional 574 MPN cases. A total of 27 sequence variants were identified in 26 patients of whom 3 had MF, 10 had CMML, 12 had aCML/MPD-U and one had HES/CEL. Microsatellite analysis across 11q indicated significant tracts of 11q copy neutral homozygosity in 11/26 CBL mutated cases. In two cases, CBL mutations were acquired as secondary events during progression of a pre-existing MPN. Patients with CBL mutations had a shorter overall survival and progression-free survival compared to mutation negative cases (OS: 33 months vs 39 months; PFS: 22 months vs 32 months) but the differences were not significant. Similarly there was no difference in gender, age, white cell count or percentage of eosinophils between mutation positive and mutation negative cases. CBL plays both positive and negative roles in tyrosine kinase signal transduction by acting as an adaptor and also a ubiquitin ligase. Of the 27 variants, 21 (78%) were missense substitutions (15 different mutations) in the region encoding the RING or linker domains, 5 (19%) were candidate splicing abnormalities involving exon 8 and one (3%) produced a stop codon. Functional analysis of selected mutations demonstrated that they abrogated CBL ubiquitin ligase activity and were transforming as assessed by the ability to confer a proliferative advantage in both liquid and semi-solid cultures of Ba/F3-FLT3 cells. We conclude that acquired, inactivating CBL mutations are a novel and widespread pathogenetic abnormality in morphologically-related, aggressive MPNs.
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Kosmider, Olivier. "Mutations of ETNK1 in aCML and CMML." Blood 125, no. 3 (January 15, 2015): 422–23. http://dx.doi.org/10.1182/blood-2014-11-609057.
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Dao, Kim-Hien, Robert H. Collins, Jorge E. Cortes, Michael W. Deininger, Brian J. Druker, Jason R. Gotlib, Tara Alyson Macey, Stephen T. Oh, Jeffrey W. Tyner, and Elliott F. Winton. "Phase 2 Study of Ruxolitinib in Patients with Chronic Neutrophilic Leukemia or Atypical Chronic Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 350. http://dx.doi.org/10.1182/blood-2018-99-119476.
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Abstract Background Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid malignancies with an estimated median survival of 2 years. No effective therapy has been established. The majority of CNL and <30% of aCML harbor an oncogenic mutation in colony stimulating factor-3 receptor (CSF3R-T618I) leading to ligand-independent activation of CSF3R and granulocytic proliferation. Preclinical studies reveal an important role for constitutive JAK/STAT signaling in disease manifestations. These data prompted our group to conduct the first clinical trial evaluating the safety and efficacy of ruxolitinib (a JAK1/2 inhibitor) in patients diagnosed with CNL and aCML. Methods The clinical trial is an open-label, phase 2 study of single agent ruxolitinib in CNL/aCML patients, regardless of CSF3R mutation status. A minimum of a 7-day washout period was required for patients on therapy aimed at reducing white blood cell count. The primary endpoint is overall response rate (partial response [PR] and complete response [CR]), which was evaluated in patients who completed 6 continuous 28-day cycles. Patients who did not reach the end of cycle 6 were considered non-responders. CR was defined as normalization of the white blood cell count, spleen volume, and marrow hyperplasia and/or dysplasia. Secondary endpoints include evaluation of ruxolitinib safety and tolerability, and clinical and laboratory correlates of response. The starting dose of ruxolitinib was guided in part by baseline platelet count. Dose modifications were allowed based on investigator discretion. Patients who remained on treatment for ongoing clinical benefit could enter an extension phase after 24 cycles of ruxolitinib treatment. Results At the time of data cutoff (October 2017), we enrolled 40 patients (median age 73.2 years; 17 females and 23 males) with a diagnosis of CNL (N=20) or aCML (N=20). The median daily starting dose was 20mg (range 10-40mg) and daily dose during the study was 30mg (range 10-50mg), administered twice daily. Twenty (50%) patients were positive for CSF3R-T618I mutation (15 CNL and 5 aCML). The median number of cycles completed was 7.0 cycles (range <1 cycle to 33 cycles). Among the 40 patients, 23 (58%) completed cycle 6 or greater, 5 (13%) have not completed cycle 6 but are in active treatment, and 12 (30%) discontinued treatment before the end of cycle 6. Disease progression and lack of clinical benefit were the main reasons for premature discontinuation of therapy. The overall response rate is 37% (13 of 35 patients: 11 PR [8 CNL and 3 aCML] and 2 CR [2 CNL]). Response rate by mutation status is 50% (10 of 20) in the CSF3R-T618I group and 15% (3 of 20) in the CSF3R-wildtype group (odds ratio 5.67, Fisher's exact p = 0.041, 95% CI: 1.05, 37.99). In those patients not achieving a CR (i.e., those with PR or stable disease [SD]), clinical benefit was observed in 33% of patients in one or more categories: hemoglobin improvement, platelet count improvement, ≥50% symptom burden reduction, and ≥50% spleen volume reduction as defined by an MDS/MPN International Working Group (Savona, et al. Blood 2015). At the end of cycle 6, 52% (11 of 21 evaluable cases) exhibited a ≥35% reduction in spleen volume. By the end of cycle 2 and 6, a mean reduction of 21% and 42%, respectively, was observed in the MPN-SAF total symptom score. Grade ≥3 anemia and thrombocytopenia were observed in 38% and 15% of patients, respectively. There was one grade ≥3 non-hematologic adverse event that was considered probably related or related to ruxolitinib (nutritional weight gain). The remaining grade ≥3 non-hematologic adverse events, including bleeding, infection, and death, were not considered probably related or related to ruxolitinib. There were 11 deaths (3 PR and 8 SD or no response). Disease progression was the most common cause of death. Conclusions Ruxolitinib provides clinical benefit in at least a third of CNL and aCML patients and is well-tolerated in this patient population. The greatest clinical benefit was among those with CSF3R-T618I mutation. However, most hematologic responses are partial in nature, reflecting a composite evaluation of the white blood cell count, spleen volume, and marrow hyperplasia and/or dysplasia. Further characterization of the clinical and genetic correlates of response, including a subset of patients with complete responses, may help optimize selection of patients for ruxolitinib therapy. Disclosures Dao: Incyte: Consultancy. Collins:Arog Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Celgene Corporation: Research Funding; Agios: Research Funding. Cortes:novartis: Research Funding. Deininger:Blueprint: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Druker:Henry Stewart Talks: Patents & Royalties; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; Novartis Pharmaceuticals: Research Funding; McGraw Hill: Patents & Royalties; Bristol-Meyers Squibb: Research Funding; Fred Hutchinson Cancer Research Center: Research Funding; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Monojul: Consultancy; Beta Cat: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Patient True Talk: Consultancy; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties. Gotlib:Incyte: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Kartos: Consultancy; Deciphera: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Oh:Gilead: Research Funding; CTI Biopharma: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Janssen: Research Funding. Tyner:Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Array: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; Aptose: Research Funding; Genentech: Research Funding; Takeda: Research Funding; Constellation: Research Funding; Gilead: Research Funding.
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SIVARAMAKRISHNAN, K. C., LUKASZ ZIAREK, and SURESH JAGANNATHAN. "MultiMLton: A multicore-aware runtime for standard ML." Journal of Functional Programming 24, no. 6 (June 18, 2014): 613–74. http://dx.doi.org/10.1017/s0956796814000161.
Full textAbstract:
AbstractMultiMLton is an extension of the MLton compiler and runtime system that targets scalable, multicore architectures. It provides specific support for ACML, a derivative of Concurrent ML that allows for the construction of composable asynchronous events. To effectively manage asynchrony, we require the runtime to efficiently handle potentially large numbers of lightweight, short-lived threads, many of which are created specifically to deal with the implicit concurrency introduced by asynchronous events. Scalability demands also dictate that the runtime minimize global coordination. MultiMLton therefore implements a split-heap memory manager that allows mutators and collectors running on different cores to operate mostly independently. More significantly, MultiMLton exploits the premise that there is a surfeit of available concurrency in ACML programs to realize a new collector design that completely eliminates the need for read barriers, a source of significant overhead in other managed runtimes. These two symbiotic features - a thread design specifically tailored to support asynchronous communication, and a memory manager that exploits lightweight concurrency to greatly reduce barrier overheads - are MultiMLton's key novelties. In this article, we describe the rationale, design, and implementation of these features, and provide experimental results over a range of parallel benchmarks and different multicore architectures including an 864 core Azul Vega 3, and a 48 core non-coherent Intel SCC (Single-Cloud Computer), that justify our design decisions.
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Marino, Christina L., Jimmy N. S. N. Tran, and Tracy Stokol. "Atypical chronic myeloid leukemia in a German Shepherd Dog." Journal of Veterinary Diagnostic Investigation 29, no. 3 (February 16, 2017): 338–45. http://dx.doi.org/10.1177/1040638716689581.
Full textAbstract:
A 4-y-old neutered male German Shepherd Dog was presented with a 3-d duration of lethargy, restlessness, and vomiting. Physical examination revealed generalized lymphadenopathy, pale mucous membranes, systolic heart murmur, dehydration, and fever. Hematologic abnormalities included moderate-to-marked leukocytosis, characterized by neutrophilia with a left shift to progranulocytes and 2% presumptive myeloid blasts, marked anemia that was nonregenerative, and marked thrombocytopenia. Dysplasia was evident in neutrophils and platelets. Bone marrow examination revealed marked myeloid and megakaryocytic hyperplasia with 7% blasts, erythroid hypoplasia, and trilineage dysplasia. Flow cytometric analysis confirmed that bone marrow cells were mostly of neutrophil lineage, with reduced expression of common leukocyte antigens (CD45, CD18) and neutrophil-specific antigen. Bone marrow cells were cytogenetically analyzed for the breakpoint cluster region–Abelson oncogene using multicolor fluorescent in situ hybridization. The genetic aberration was present in 7% of cells, which was a negative result (>10% of cells is considered positive). Euthanasia was elected. Histologic examination showed extensive infiltration of multiple organs by neoplastic myeloid cells, with effacement of lymph node and splenic architecture. The final diagnosis was atypical chronic myeloid leukemia (aCML), an uncommon myeloproliferative disorder with features of myelodysplastic syndromes (dysplasia) and chronic leukemia (neutrophilic leukocytosis with <20% marrow blasts, extramedullary infiltrates). The trilineage dysplasia, lack of monocytosis, and supporting cytogenetics distinguish aCML from CML, chronic neutrophilic leukemia, and chronic myelomonocytic leukemia.
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Ernst, Thomas, Andrew Chase, Claire Hidalgo-Curtis, Katerina Zoi, Christine Zoi, Andreas Hochhaus, Andreas Reiter, William Vainchenker, Francis Grand, and Nicholas C. P. Cross. "Frequent Inactivating Mutations of TET2 and CBL Are Associated with Acquired Uniparental Disomy in Atypical Chronic Myeloid Leukemia and Related Disorders." Blood 114, no. 22 (November 20, 2009): 3258. http://dx.doi.org/10.1182/blood.v114.22.3258.3258.
Full textAbstract:
Abstract Abstract 3258 Poster Board III-1 Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) such as atypical BCR-ABL negative chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML) combine dysplastic morphology with features of a CML-like myeloproliferative disorder. The underlying pathomechanism of these related disorders is poorly understood. Recent evidence has shown that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. In this study we sought to investigate if aUPD characterizes MDS/MPN of unknown molecular etiology, and whether it could be used as a tool to help identify novel driver mutations. Genome wide high resolution SNP 6.0 array analysis was performed on total leukocyte DNA from 148 patients with aCML (n=54), CMML (n=69), and unclassified MDS/MPN (n=25). All patients were negative for BCR-ABL, JAK2 V617F, FIP1L1-PDGFRA and cytogenetic indicators of other tyrosine kinase fusion genes. Homozygous copy neutral SNP calls >20 Mb, considered indicative of aUPD, were seen in 39 (26%) patients. In total, 15 different chromosomes were involved with the most common recurrent abnormalities being seen at 4q (n=7), 7q (n=12), and 11q (n=8). Sequencing of candidate genes in the minimally affected regions excluded the involvement of tyrosine kinases and several other genes. Following the identification of TET2 at 4q24 as a putative novel tumor suppressor gene of unknown function in patients with classic MPN and MDS we identified homozygous TET2 variants in 6 cases with 4q aUPD. Analysis of 210 additional patients revealed TET2 variants in aCML (16/53; 30%), CMML (28/70; 40%), unclassified MDS/MPN (5/17, 29%), hypereosinophilic syndrome (4/30; 13%) but none in blast crisis CML (n=40). In total, 70 TET2 variants were identified that were spread throughout the coding region. Of these, 35 were likely causative changes predicted to result in premature chain termination (nonsense, n=18; deletion, n=10; insertion, n=7) and 35 were missense substitutions that have not been reported as SNPs. 20 missense mutations (57%) clustered in two conserved regions. TET2 mutations were not associated with a change of overall or progression-free survival compared to mutation negative cases. Mutations in CBL, encoding a key regulator of tyrosine kinase signaling, were identified in 5 cases with 11q aUPD and analysis of 574 additional MPN and MDS/MPN patients revealed a total of 27 CBL variants in 26 patients with aCML (12/152; 8%), CMML (10/78; 13%), myelofibrosis (n=3/53; 6%) or hypereosinophilic syndrome (n=1/96; 1%). Most variants were missense substitutions in exons 8 or 9 (encoding the linker/RING domain) that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells that overexpressed FLT3. Patients with CBL mutations had a shorter overall survival and progression-free survival compared to mutation negative cases (OS: 33 months vs. 39 months; PFS: 22 months vs 32 months) but the differences were not significant. We conclude that aUPD is common in atypical CML and related disorders and that inactivating mutations of TET2 and CBL are associated with aUPD at 4q and 11q, respectively. Disclosures: Hochhaus: Novartis: Honoraria; BMS: Honoraria.
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Bernasconi, Paolo, Irene Dambruoso, Marina Boni, Paola Maria Cavigliano, Ilaria Giardini, Barbara Rocca, Rita Zappatore, et al. "Rearrangements of Tyrosine Kinase (TK) Genes in Chronic Myeloproliferative Disorders (CMPD): A FISH Study." Blood 128, no. 22 (December 2, 2016): 5493. http://dx.doi.org/10.1182/blood.v128.22.5493.5493.
Full textAbstract:
Abstract CMPDs are heterogeneous hematopoietic stem cell disorders caused by the constitutive activation of specific TK genes induced by mutations or, exceptionally, chromosomal translocations that often escape conventional cytogenetics (CC) identification as they often involve poorly stained regions. The demonstration of these TK gene rearrangements is twofold relevant: diagnostically, as these translocations identify specific entities within the 2016 WHO classification of CMPDs and clinically, as most TK can be targeted with specific TK inhibitors. Thus, this study employed FISH probes specific for TK genes to establish the incidence of these chromosomal translocations, to identify uncommon TK translocation partners, to establish whether eosinophils are part of the clonal cell population and to find any potential correlation with clinical parameters and outcome. From January 2005-December 2015 43 consecutive patients (pts) were analysed; 13 females and 31 males with a median age of 47 years (range 22-72). According to WHO classification, 20 pts were diagnosed as atypical chronic myeloid leukemia (aCML), 22 as chronic eosinophilic leukemia (CEL) and one as AML/T lymphoblastic lymphoma (T-LL). Median follow-up was 39 months (range 8-136). At the time of the study one pt died and one experienced disease progression. FISH probes were obtained from Kreatech (Amsterdam, NL), Abbot Molecular Inc. (Chicago, Il, USA) and from BACPAC Resources Center at C.H.O.R.I. (Oakland, USA) after determining their Mb position using UCSC genome browser on Human Feb. 2009 assembly. The commercial probes, applied according to manufacturer's guidelines were: ON FIP1L1-CHIC2-PDGFRA (4q12) Del, Break; ON PDGFRB (5q33) Break; ON FGFR1 (8p12) Break; ON JAK2 (9p24) Break; LSI BCRABL. The BAC probes RP11-484L21 and RP11-880I16 covering the PCM1 gene were labelled and applied as previously described. i-FISH, cut-off values were obtained from the analysis of 300 nuclei from ten normal samples and were fixed at 10%. An abnormal FISH pattern was revealed in 12 pts (27.9%): 5/20 (25%) with aCML, 6/22 (27.2%) with CEL and one with AML/T-LL. Two aCML pts presented a trisomy 8, one a t(9;13)(q34;q14) which involved the ABL gene and a not yet identified partner gene, one at(9;22)(p24;q11) which involved the ABL and BCR genes and one a t(8;22)(p11;q11) which involved the FGFR1 gene. Interestingly, after one month this last pt progressed to AML and on CC showed a duplication of the derivative chromosome 8. Two CEL pts showed a JAK2 rearrangement: one who carried a t(8;9)(p22;p24) on CC displayed the classical PCM1-JAK2 gene fusion, the other who carried a t(3;8)(?;p24) not revealed by CC harboured a fusion between the JAK2 gene and a not yet identified partner. Three additional CEL pts showed a PDGFRB rearrangement which escaped CC detection too. In these pts who on CC showed a t(1;5)(?;q33) with loss of the reciprocal translocation product, a t(5;8)(q33;?) and a t(5;12)(q33;?), the PDGFRB translocation partner has been not yet identified. The last chromosomally normal CEL pt showed a PDGFRA deletion. Thus, in 4 pts FISH with BAC probes is still on-going in order to search the unknown translocation partners of the JAK2 and PDGFRB genes. Noteworthy, despite the fact that all these pts presented a relevant peripheral eosinophilia (≈65%), FISH performed on peripheral blood smears always revealed a normal pattern. The sole AML/T-LL pt who carried a t(8;13)(p11;q12) which produced the classical FGFR1-ZNF198 gene fusion failed to respond to conventional chemotherapy and died of disease related complications. From a clinical point of view 3 aCML/CEL pts with TK rearrangements responded to TK inhibitors experiencing a haematological improvement including one complete remission (CR); the t(8;22) positive pt entered CR after induction chemotherapy. In conclusion, i) FISH effectively reveals cryptic TK translocations in about 36% of chromosomally normal CMPDs; ii) these rearrangements are more common in CELs than in aCML; iii) peripheral blood eosinophils may show a normal FISH pattern; iv) FISH can effectively be used to monitor the clonal cell population during disease outcome. Disclosures No relevant conflicts of interest to declare.