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Manaila, Roxana, Vlad Moisoiu, Erik Knutsen, Mihnea P. Dragomir, and George A. Calin. "Diagnostic and Therapeutic MicroRNAs in Primary Myelofibrosis." Proceedings of the Singapore National Academy of Science 14, no. 02 (2020): 91–109. http://dx.doi.org/10.1142/s2591722620400074.
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Primary myelofibrosis (PMF) is a pluripotent hematopoietic stem cell-derived malignancy, included in the heterogeneous group of myeloproliferative neoplasms (MPNs). PMF diagnosis is based on a composite assessment of clinical and laboratory data. The three major diagnostic criteria are: screening for driver mutations, exclusion of other conditions that can cause myelofibrosis, and bone marrow biopsy displaying megakaryocyte changes and fibrosis. PMF treatment options are only partially disease-modifying and consist mainly of symptom control. Recently, a new targeted therapy was introduced for PMF patients, JAK-STAT inhibitors (i.e. ruxolitinib). However, specific subgroups of patients do not benefit from the JAK-STAT inhibitors: (1) those who are carrying JAK2 mutations, but ruxolitinib does not reduce the spleen size; (2) triple negative patients (no JAK2, CALR, or MPL mutations); and (3) those who discontinue JAK-STAT therapy because of side effects. These subgroups are in need of new therapeutic approaches. Mature microRNAs (miRNAs) range from 16 to 28 nucleotides (nt) in length and regulate specific messenger RNAs at the post-transcriptional level. Numerous in vitro and in vivo studies have reported specific miRNAs, as well as complex miRNA networks, to be dysregulated in PMF. Several of these miRNAs were shown to be implicated in essential events of PMF pathophysiology: increase of bone marrow fibrosis, progression to acute myeloid leukemia, resistance to JAK-STAT inhibitors, and activation of differentiation of hematopoietic stem/progenitor cells into megakaryocytes. Hence, we propose miRNAs as a potential minimally invasive diagnostic tool for PMF and as therapeutic targets that could address the unmet medical needs of these patients.
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Norfo, Ruggiero, Roberta Zini, Valentina Pennucci, et al. "Regulatory Mrna/Microrna Networks in CD34+ Cells From Primary Myelofibrosis." Blood 120, no. 21 (2012): 2854. http://dx.doi.org/10.1182/blood.v120.21.2854.2854.
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Abstract Abstract 2854 Molecular mechanisms underlying Philadephia-negative myeloproliferative neoplasm (MPN) pathogenesis were partially unraveled in 2005–2006 with the identification of somatic gain-of-function of JAK2 and MPL, after which many other mutated genes were found. Recently, several new molecular pathogenetic mechanisms were identified. Among them, aberrant microRNA (miRNA) expression especially seems to add to the molecular complexity of MPNs, as specific miRNA signatures capable of discriminating MPN cells from those of normal donors were previously reported (P. Guglielmelli et al., Exp Hematol, 2007). In order to have a comprehensive picture of miRNA deregulation and its relationship with differential gene expression in primary myelofibrosis (PMF) cells, we obtained coding gene- (GEP) and miRNA expression profiles (miEP) in the same CD34+ sample from 31 healthy donors and 42 PMF patients by means of Affymetrix technology (HG-U219 and miRNA 2.0 arrays). 726 genes were found as differentially expressed (DEG) (fold change contrast ≥2, false discovery rate ≤0.05) (FIG. 1) and further analysis pointed out that several DEG are related to processes involved in PMF progression as megakaryocyte (MK) differentiation, fibrosis and migration. Of interest, we found the upregulation of some putative cancer markers, such as WT1 (K. Inoue et al., Blood, 1994) and ANGPT1 (C.L. Cheng, Br J Cancer, 2011) whose expression has already been associated with poor prognosis in hematological neoplasms and in other malignancies. Figure 1 Figure 1. Among the deregulated transcription factors, we detected several genes involved in CD34+ commitment, and potentially in their transformation, such as NFE-2 (C. LAbbaye et al., J Clin Invest, 1995) and KLF3 (A.P. Funnell, Mol Cell Biol, 2012). As regards miEP, we achieved a list of 74 human miRNAs modulated in PMF (DEM) (fold change contrast ≥1.5, false discovery rate ≤0.05), some of which associated with hematological malignancies or known as oncomirs are upregulated, i.e. hsa-miR-155-5p (S. Jiang, Cancer Res, 2010), miRNAs belonging to the miR-17–92 cluster (L. Venturini et al., Blood, 2007), whereas other aberrantly expressed miRNAs have never been described in any hematological context. Next, we performed an in silico integrative analysis (IA) with Ingenuity Pathway analysis software, which combines the computational predicted targets with the gene expression data, in order to construct regulatory networks of the functional human miRNA-target interactions. IA between DEG and DEM disclosed a high number of predicted targets with anti-correlated expression to the trend of their targeting miRNAs. This approach allowed the identification of different networks potentially involved in PMF onset and progression, such as MK differentiation and chromatin remodeling, highlighting the potential contribution of miRNAs to PMF pathogenesis. In particular, the integrative analysis has identified an interaction network involving the oncomirs miR-155-5p and miR-29a-3p (R. M. O'Connel et al, J Exp Med, 2008, Y.C. Han et al, j Exp Med, 2010) and their targets (FIG. 2). Figure 2 Figure 2. In this network the upregulation of miR-155-5p and mir-29a-3p could explain the negative regulation of two tumor suppressor genes, HBP1 and TP53INP1, and of SPTB1, CDC42 and KLF3, whose downregulation is involved in malignant hematopoiesis (L.Yang et al, Blood 2007). This network also shows the upregulation of some miRNAs whose function is unknown in the hematopoietic context as miR-335-5p, with the negative regulation of its predicted targets, NR4A3 and PRDM2, which are described as implicated in myeloproliferation (AM Ramirez-Herrick et al, Blood 2001). The present findings lay the groundwork for functional in vitro validation of selected networks in normal and PMF CD34+ cells by means of DEG/DEM overexpression and silencing experiments; furthermore, expression data will be helpful in order to find a clinical correlation between mRNA/miRNA expression levels and diagnostic/prognostic relevance. In conclusion, GEP and miEP pointed out genes and miRNAs candidate for elucidating some of the pathogenetic features of PMF CD34+ cells, whereas IA uncovered potential regulatory networks in which aberrantly expressed miRNAs and genes interact contributing to the malignant phenotype. Disclosures: Vannucchi: Novartis: Membership on an entity's Board of Directors or advisory committees.
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Zini, Roberta, Ruggiero Norfo, Valentina Pennucci, et al. "Integrative Analysis Of mRNA/miRNA Expression Profiles Identified JARID2 As a Shared Target Of Deregulated Mirnas In Primary Myelofibrosis." Blood 122, no. 21 (2013): 1600. http://dx.doi.org/10.1182/blood.v122.21.1600.1600.
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Abstract Ph-negative myeloproliferative neoplasms (MPNs) are characterized by many somatic mutations which have already been shown useful in the prognostic assessment of MPN patients [A.M. Vannucchi et al., Leukemia, 2013]. Moreover, aberrant microRNA (miRNA) expression seems to add to the molecular complexity of MPNs, as specific miRNA signatures capable of discriminating MPN cells from those of normal donors were previously reported [P. Guglielmelli et al., Exp Hematol, 2007]. In order to have a comprehensive picture of miRNA deregulation and its relationship with differential gene expression in primary myelofibrosis (PMF) cells, we obtained gene- (GEP) and miRNA expression profiles (miEP) of CD34+ cells from 31 healthy donors and 42 PMF patients using Affymetrix technology (HG-U219 and miRNA 2.0 arrays). Among 726 differentially expressed genes (DEG) we found that several putative cancer markers (WT1, ANGPT1) and several genes related to PMF progression, i.e. involved in megakaryocyte (MK) differentiation (NFE2, CD9), and fibrosis development (DLK1, LEPR1), were significantly more expressed in PMF samples than in the normal counterpart. Similarly, as regards the miEP, among 74 human differentially expressed miRNAs (DEM) in PMF compared to controls we found the upregulation of several miRNAs associated with hematological malignancies or known as oncomiRs (i.e. hsa-miR-155-5p [S. Jiang et al., Cancer Res, 2010], miRNAs belonging to the miR-17-92 cluster [L. Venturini et al., Blood, 2007]), and other aberrantly expressed miRNAs never described in hematopoiesis (i.e. hsa-miR-335-5p). Then, in order to construct regulatory networks of the functional human miRNA-target interactions, we performed an integrative analysis (IA) with Ingenuity Pathway analysis software, which combines the miRNA expression profile with computational predicted targets and with the gene expression data. IA between DEG and DEM disclosed a high number of predicted targets with anti-correlated expression to the trend of their targeting miRNAs. Of note, IA identified an interaction network (see Figure) in which the upregulated oncomirs miR-155-5p [R.M. O'Connel et al., J Exp Med, 2008], miR29a-3p [Y.C. Han et al., J Exp Med, 2010] and miR-19b-3p [K.J. Mavrakis et al., Nat Cell Biol, 2010] could explain the downregulation of targets whose lower expression was already described as involved in myeloproliferative phenotypes, such as NR4A3, CDC42, HMGB3. Additionally, IA disclosed the chromatin remodeler JARID2, which is frequently deleted in leukemic transformation of chronic myeloid malignancies, as a shared target of several upregulated miRNAs in PMF samples (i.e. miR-155-5p, miR-152-3p). Noteworthy, these miRNA-mRNA interactions were functionally confirmed by 3' UTR luciferase reporter assays. Next, in order to characterize the role of JARID2 in PMF pathogenesis, we performed RNAi-mediated gene silencing experiments on CD34+ cells of healthy donor. Interestingly, inhibition of JARID2 expression produces in silenced cells a significant increase of CD41 expression when compared with control (28.6±3.1% vs 15.3±1.8% at day 8, 52.6±7.6% vs 35.4±4.9% at day 12 of serum free liquid culture) and a remarkable increase in CFU-MK colonies (59.6±6.5% vs 39.8±5.9%). The values are reported as mean ± 2S.E.M from five independent experiments. Moreover, morphological analysis after May-Grunwald-Giemsa staining showed that JARID2 silencing induces in normal CD34+ cells a considerable enrichment in MK precursors at different stages of maturation. This study allowed the identification of different networks possibly involved in PMF onset, highlighting the potential contribution of miRNAs to PMF pathogenesis. Furthermore, for the first time, we demonstrated that the JARID2 downregulation in CD34+ cells might contribute to the abnormal megakaryopoiesis typical of PMF. Disclosures: Rambaldi: Novartis: Honoraria; Sanofi: Honoraria; Italfarmaco: Honoraria.
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Harada, Kayo Shirado, Kazuhiko Ikeda, Kazuei Ogawa, et al. "The Role Of Deregulated HMGA2 Expression With Promoter Methylation Of p16 In Myeloproliferative Neoplasms." Blood 122, no. 21 (2013): 1606. http://dx.doi.org/10.1182/blood.v122.21.1606.1606.
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Abstract Myeloproliferative Neoplasms (MPNs) are characterized by clonal proliferative hematopoiesis with increased mature blood cells. The signal-activating mutations such as JAK2V617F increase blood cells, but it remains uncertain how an abnormal hematopoietic cell clone expands in MPNs. We have recently showed that overexpression of the high mobility group AT-hook 2 (HMGA2) causes proliferative hematopoiesis with providing a clonal growth advantage to hematopoietic cells in mice (Ikeda et al, Blood, 2011), suggesting the possibility that HMGA2 contributes to the pathogenesis of MPNs. However, since only a few studies have evaluated expression of HMGA2 mRNA in patients with MPNs, the role of HMGA2 in the pathogenesis of MPNs is yet unclear. MPNs also show mutations in epigenetic modifiers involving DNA methylation such as polycomb group genes (PcG) and aberrant expressions of micro RNAs (miRNA) that negatively regulate expressions of targeted genes. Interestingly, deficiency in either PcG-related BMI1 (Oguro et al, J Exp Med, 2012) or let-7-family miRNA (Mayr et al, Science, 2007) causes deregulation of HMGA2 expression, leading to its oncogenic activity in part by negatively regulating tumor suppressor p16. Thus, in this study, to clarify the role of HMGA2 in MPNs, we investigated expression of HMGA2 mRNA in peripheral granulocytes of 56 patients with MPNs including 23 polycythemia vera (PV), 26 essential thrombocythemia (ET) and 7 primary myelofibrosis (PMF) along with clinical findings, JAK2V617F allele burden, expressions of BMI1 mRNA and let-7-family miRNAs, and promoter methylation of p16. Quantitative RT-PCR (qPCR) showed significantly higher expression of HMGA2 mRNA relative to internal control HPRT1 mRNA in PMF (mean ± SD; 31.7 ± 42.8, p<0.01), but not PV (15.7 ± 53.2) or ET (2.14 ± 7.70), compared with 12 healthy volunteers (HV; 0.431 ± 0.366). In addition, deregulated HMGA2 expression (>1.2), which was determined as relative expression level above mean + 2SD of HMGA2 mRNA in 12 HV, was most frequently detected in patients with PMF [7/7 (100%)] (p<0.01), compared with PV [5/23 (21.7%)] and ET [6/26 (23.1%)]. We also found a significant positive correlation in expression levels of HMGA2 mRNA with serum LDH values (r=0.531, p<0.01) rather than JAK2V617F allele burden (r=0.25, p=0.08). These data suggested that expression of HMGA2 mRNA independently correlated with disease phenotype and status in MPNs. We next explored the cause of deregulated expression of HMGA2 mRNA and found lower expression of let-7a (0.19 ± 0.13 vs. 0.42 ± 0.39, p=0.04) and -7c (0.57 ± 0.60 vs. 1.14 ± 0.94, p=0.06) rather than -7b (p=0.2) by qPCR, in patients with deregulated expression of HMGA2 mRNA compared with other patients. However, HMGA2-involved chromosomal abnormality in 12q13-15 was not detected in any patient, and there was no difference in expression of BMI1 mRNA between patients with deregulated expression of HMGA2 mRNA and other patients. Thus, decreased expression of let-7 miRNAs might contribute to deregulated expression of HMGA2 mRNA in MPNs. Finally, we investigated correlation of deregulated expression of HMGA2 mRNA with promoter methylation of p16. Methylation-specific PCR assay detected promoter methylation of p16 in 17/56 (30.4%) patients with MPNs. Strikingly, patients with deregulated expression of HMGA2 mRNA significantly more often showed promoter methylation of p16 compared with other patients [10/18 (55.6%) vs. 7/38 (18.4%), p<0.01]. Furthermore, patients with promoter methylation of p16 showed higher expression levels of HMGA2 mRNA than patients without the methylation, especially in patients with PMF (2.33 ± 0.90 vs. 70.9 ± 38.3, p=0.01). In conclusion, deregulated expression of HMGA2 in association with decreased expression of let-7 miRNAs may play a crucial role in the pathogenesis of MPNs possibly through p16. Disclosures: No relevant conflicts of interest to declare.
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Rontauroli, Sebastiano, Ruggiero Norfo, Valentina Pennucci, et al. "MiR-494-3p Overexpression Leads to SOCS6 Downregulation and Supports Megakaryocytopoiesis in Primary Myelofibrosis CD34+ Hematopoietic Stem/Progenitor Cells." Blood 128, no. 22 (2016): 4272. http://dx.doi.org/10.1182/blood.v128.22.4272.4272.
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Abstract Primary Myelofibrosis (PMF) belongs to the Philadelphia negative Myeloproliferative Neoplasms (MPNs) and is characterized by hematopoietic stem-cell derived clonal myeloproliferation, involving especially megakaryocyte (MK) lineage, bone marrow fibrosis and extramedullary hematopoiesis. Recent studies have suggested that alterations in miRNAs expression could play a critical role in MPN's pathogenesis. In order to shed some light on this issue, we have previously performed the integrative analysis (IA) of gene and miRNA expression profiles of PMF CD34+ hematopoietic stem/progenitor cells (HSPCs) isolated from 42 PMF patients compared with 31 healthy donors (R. Norfo et al., Blood, 2014). IA identified miR-494-3p as one of the most upregulated miRNAs in PMF CD34+ cells associated to the highest number of downregulated predicted targets (eighty-six, Fig. 1). In order to study the role of miR-494-3p in hematopoietic commitment and differentiation, and to elucidate its possible involvement in PMF pathogenesis, we performed miRNA overexpression experiments in cord blood (CB) CD34+ cells through miRNA mimic electroporation. The data showed that miR-494-3p promotes MK differentiation of HSPCs. Indeed, the fraction of cells expressing MK surface antigen CD41 was steadily increased in miR-494-3p overexpressing samples compared with controls (75.4±0.3% vs 53.2±3.5% at day 8, 82.6±1.3% vs 60.4±4.3% at day 10 of culture, p<0.05), as well as the percentage of cells expressing the late MK antigen CD42b was similarly increased. Furthermore, the percentage of MK colonies was increased in collagen-based clonogenic assay upon miR-494-3p overexpression compared to control (44.8±4.1% vs 24.1±2.1%, p<0.05). Next, to better characterize the molecular mechanisms underlying megakaryocytopoiesis stimulation by miR-494-3p, we profiled CB CD34+ cells overexpressing this miRNA using the Affymetrix HG-U219 microarray platform. Gene Expression profile analysis allowed the identification of 134 differentially expressed genes between cells overexpressing miR-494-3p and controls. In particular, we highlighted the presence of 13 genes downregulated both upon miRNA overexpression and in PMF CD34+ cells. Among them, Suppressor of Cytokine Signaling 6 (SOCS6) turned out to be the miR-494-3p predicted target associated to the most favorable prediction scores according to TargetScan, microRNA.org and miRDB prediction algorithms. Furthermore, 3' UTR luciferase reporter assays, performed in K562 cell line, proved the predicted interaction between miR-494-3p and SOCS6 3'UTR. Subsequently, we studied the role of SOCS6 in HSPCs differentiation by inhibiting its expression in CB CD34+ cells through small interfering RNAs. SOCS6 silencing stimulated megakaryocytopoiesis in CB CD34+ cells, as demonstrated by the expansion of CD41+ and CD42b+ cell fractions in SOCS6 silenced samples compared with controls (52.8±7.0% vs 37.7±4.5% at day 8, 66.9±7.2% vs 50.7±7.2% at day 10 for CD41+ cells, p<0.05). Moreover, MK colonies were increased upon SOCS6 silencing in collagen-based clonogenic assays (62.4±7.7% vs 51.3±6.5%, p<0.05) and morphological analysis further supported these results. Finally, in order to study the possible contribution of miR-494-3p overexpression to PMF pathogenesis, we performed inhibition experiments in PMF CD34+ cells by means of miR-494-3p antagomiR. As a result, miR-494-3p silencing led to SOCS6 upregulation and impaired MK differentiation in PMF HSPCs as demonstrated by the decrease in CD41+ cell fraction in silenced samples compared with controls (28.6±7.1% vs 39.2±7.7% at day 12 of culture, p<0.05) and by the reduction of MK colonies in collagen-based clonogenic assay (44.4±3.6% vs 54.7±2.5%, p<0.05). The values are reported as mean±S.E.M from 3 independent experiments. Taken together, our results showed that miR-494-3p overexpression promotes megakaryocytopoiesis in HSPCs. Moreover, we demonstrated for the first time that SOCS6 is a direct target of miR-494-3p. Since SOCS6 downregulation promotes MK differentiation of HSPCs, SOCS6 could be considered, at least in part, responsible for the biological effects observed after miR-494-3p overexpression. As miR-494-3p and SOCS6 showed the same expression trend in PMF CD34+ cells, our results could suggest that miR-494-3p/SOCS6 axis is involved in the induction of MK hyperplasia typically observed in PMF patients. Figure Figure. Disclosures Vannucchi: Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau.
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Harada, Kayo Shirado, Kazuhiko Ikeda, Kazuei Ogawa, Hiroshi Ohkawara, and Yasuchika Takeishi. "Dysregulation of the Let-7/HMGA2 Axis with Methylation of p16 Promoter As a Possible Target of Histone Deacetylase Inhibitor in Myeloproliferative Neoplasms." Blood 124, no. 21 (2014): 3213. http://dx.doi.org/10.1182/blood.v124.21.3213.3213.
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Abstract Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), are clonal hematological disorders characterized by proliferation of mature blood cells. Recently, several agents that influence epigenetic modifications, such as histone deacetylase inhibitors (HDACi), as well as JAK2 inhibitors, have been investigated for high-risk MPNs. For example, an HDACi, panobinostat has shown significant efficacy including nearly complete response in PMF (Mascarenhas et al, BJH, 2013), but molecular targets of HDACi remain largely unknown. The High Mobility Group AT-hook 2 (HMGA2) is a non-histone chromatin protein that modulates transcriptions of various genes and contributes to chromatin modification and epigenetic regulation including DNA methylation (Fusco et al, Nat Rev Cancer, 2007; Sun et al, PNAS 2013). Let-7 micro RNAs (miRNAs) negatively regulate expression of HMGA2 through 3’UTR of HMGA2 mRNA, although HMGA2 mRNA consists of both the major variant containing 3’UTR with let-7-specific sites (variant 1) and some minor variants without 3’UTR. We previously reported that overexpression of HMGA2 due to transgenic expression of Hmga2 cDNA without 3’UTR caused proliferative hematopoiesis with providing a clonal advantage to hematopoietic stem cells in mice (Ikeda et al, Blood, 2011). We also showed a deregulation of HMGA2 mRNA expression due to reduced let-7 miRNA level in granulocytes from patients with almost all of PMF and over 20% of PV and ET (Harada-Shirado et al, Blood [Abst], 2013), being associated with splenomegaly, elevated serum LDH values, and methylation of p16 promoter. Thus, we hypothesized that HMGA2 may be a candidate gene as a therapeutic target in MPNs. Since association of HDAC with HMGA2 has been reported in cord blood-derived cells (Lee et al, Cell Mol Life Sci, 2011), we here studied effects of the panobinostat on expressions of HMGA2 and let-7 in HMGA2-expressing myeloid cells including PMF-derived CD34+ cells. First, we found significantly higher HMGA2 mRNA levels in CD34+ cells from 2 PMF patients compared with CD34+ cells from 2 healthy individuals (P<0.001), as well as U937 cells compared with HL60 cells (P<0.001). Thus, we used CD34+ cells from one of these 2 PMF patients and U937 cells for further experiments. Interestingly, treatment with panobinostat at the concentration of 40 nM for 8 hours significantly increased expressions of let-7a (P<0.001 and P=0.003, respectively), -7b (P<0.001 and P<0.001), and -7c (P<0.001 and P=0.06) in U937 cells and PMF CD34+ cells, compared with samples without the treatment. In contrast, Western blotting showed clearly reduced expression of HMGA2 protein in U937 cells after the treatment with panobinostat. Moreover, we found that variant 1 of HMGA2 mRNA with 3’UTR was significantly reduced by the treatment with panobinostat, compared with samples without the treatment in both U937 cells and PMF CD34+ cells (P<0.001 and P<0.001, respectively), while expression levels of variant 2 lacking let-7-specific sites were not changed by the treatment. These findings strongly suggested that panobinostat decreased expression of HMGA2 through 3’UTR of HMGA2 mRNA by increasing expressions of let-7 miRNAs. Of note, we next found much higher expression of variant 1 of HMGA2 mRNA than variant 2 in granulocytes from 15 of 17 (88%) MPN patients whose HMGA2 mRNA levels were higher than controls in our previous study (Blood [Abst], 2013). We also assessed if treatment by panobinostat for the dysregulated let-7/HMGA2 axis may be a therapeutic option for MPNs with respect to DNA methylation. Panobinostat treatment substantially reduced the expressions of DNMT1 and DNMT3a as well as HMGA2 proteins, significantly demethylated the p16 promoter (P<0.001), and decreased survival (P<0.001) in U937 cells. Moreover, knocking-down of HMGA2 with small interfering RNA in U937 cells significantly increased expression of TET3 mRNA and demethylated the p16 promoter, suggesting that HMGA2 expression may contribute to methylation of the p16 promoter. In conclusion, deregulated expression of HMGA2 due to downregulation of let-7 miRNAs, which may lead to some epigenetic modifications such as methylation of the p16 promoter, is a possible therapeutic target of HDACi in MPNs. Disclosures Ikeda: Novartis Pharmaceuticals: Other.
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Visani, Giuseppe, Alessandro Isidori, Maria Rosaria Sapienza, et al. "Identification of Novel Cryptic Chromosomal Abnormalities in Primary Myelofibrosis by Single-Nucleotide Polymorphism Oligonucleotide Microarray." Blood 114, no. 22 (2009): 1890. http://dx.doi.org/10.1182/blood.v114.22.1890.1890.
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Abstract Abstract 1890 Poster Board I-913 Background. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm (MPN) characterised by a proliferation of predominantly megakaryocytes and granulocytes in bone marrow that in fully developed disease is replaced by fibrous tissue. At molecular level, no specific defect has been identified yet. Cytogenetic abnormalities occur in up to 30% of patients, the commonest including del(13)(q12-22), der(6)t(1;6)(q21-23;p21.3), del (20q), and partial trisomy 1q. In addition, approximately 50% of patients with PMF exhibit a single, recurrent, somatic mutation in the gene encoding the cytoplasmic tyrosine kinase Janus kinase 2 (JAK2). However, such mutation is not specific, also occurring in other MPN. Recently a couple of reports dealt with single-nucleotide polymorphism (SNP) array karyotyping of MPD, including some PMF. Importantly, such studies could identify previously uncovered genetic lesions, highlighting the importance of novel high resolution technologies for the detection of formerly unknown, cryptic aberrations. In this study we performed high resolution karyotyping by SNP oligonucleotide microarray by using the most updated Affymetrix array (Genome-Wide Human SNP Array 6.0) in 20 cases of myelofibrosis (MF) in order to identify novel cryptic genomic aberrations. Methods. DNA (500 ng) was extracted from peripheral blood cells (PBMNC) of 14 primary and 6 secondary MF patients. PBMNC were depleted from lymphocytes by magnetic beads. Briefly, CD3+ cells were labeled with anti-CD3 MoAb directly coupled to magnetic microbeads (Miltenyi Biotech), washed and subsequently purified using Mini-MACS technology. After selection, cell present in the positive (CD3) and negative (PBMNC) fractions were counted and submitted to flow cytometry analysis. DNA was processed and hybridized to the Affymetrix SNP arrays 6.0 as for manufacturer instruction. A whole-genome copy number variation (CNV), genotyping, loss of heterozygosity (LOH) and uniparental disomy (UPD) analyses were performed using the Partek Suite 6.0. Ten lab-specific as well as 90 HapMap samples relative to Caucasian healthy donor were used as control reference. Genomic abnormalities were defined as recurrent when occurring in at least 25% of cases. JAK2 mutational status was assessed as reported, by alle-specific PCR. Clinical information and complete follow up were retrieved for all cases. Direct sequencing, FISH, qPCR and immunohistochemistry (IHC) has been chosen for validation. Results. In all patients we could detect several CNV. The median number of CNV was 60 (range, 34-72), including 46 amplifications (A) and 14 deletions (D). All commonest previously described abnormalities were detected. In addition, several formerly uncovered recurrent lesions were identified, mainly involving 1p, 1q, 2p, 4p, 4q, 5q, 6p, 6q, 7q, 8p, 9q 10q, 11p 11q, 12p, 14q, 15q, 16p, 16q, 17q, 18q, 19q, 20p, 22q. The median size of such CNV was 424,582 Kbp (1,379 Kbp-71,277 Mbp). We then compared JAK2+ vs. JAK2− cases. Of note, we found numerous definite aberrations (A or D) distinguishing the two groups and specifically affecting 16q23.1, 1p36.13, 3q26, 14q13.2, 5q33.2, 6q14.1, 7q33, 8p23.1, and 9p11.2. Grippingly, several genes of potential interest for PMF pathogenesis were identified within the involved loci, including RET, SCAPER, WWOX and SIRPB1. Among others, the product of such genes has been selected for validation by IHC. Similarly, many miRNA were recognized, which may deserve further investigation. Conclusions. By using a newly developed highly sensitive array we identified novel cryptic lesions in patients affected by MF. Future studies on larger series, as well as functional analyses will definitely assess their role in the pathogenesis of the disease. Of note, consistent differences were recorded in JAK2+ vs. JAK2−, supporting the hypothesis of different genetic mechanisms occurring in the two sub-groups. Acknowledgments: this work was supported by AIL Pesaro Onlus, Centro Interdipartimentale per la Ricerca sul Cancro “G. Prodi”, BolognAIL, AIRC, FIRB, RFO, Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte e Ravenna, Progetto Strategico di Ateneo 2006.*GV and MRS equally contributed to this work. Disclosures: No relevant conflicts of interest to declare.
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Costa Villela, Neysimelia, Gustavo Zamperlini, Patrícia Shimoda Ikeuti, Roseane Vasconcelos Gouveia, Simone De Castro Resende Franco, and Luiz Fernando Lopes. "Myeloproliferative neoplasms." JOURNAL OF BONE MARROW TRANSPLANTATION AND CELLULAR THERAPY 2, no. 4 (2021): 129. http://dx.doi.org/10.46765/2675-374x.2021v2n4p129.
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 In addition to the chronic myeloid leukemia (CML) BCR-ABL1+, classic myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia and primary myelofibrosis. These have a very low incidence in the pediatric age group and there is no consensus on treatment in children.
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Stein, Brady L., and Alison R. Moliterno. "Primary Myelofibrosis and the Myeloproliferative Neoplasms." JAMA 303, no. 24 (2010): 2513. http://dx.doi.org/10.1001/jama.2010.853.
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Kiladjian, Jean-Jacques. "The spectrum of JAK2-positive myeloproliferative neoplasms." Hematology 2012, no. 1 (2012): 561–66. http://dx.doi.org/10.1182/asheducation.v2012.1.561.3807838.
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Abstract The discovery of the JAK2V617F mutation triggered an unexpected flowering of basic and clinical studies in the field of myeloproliferative neoplasms (MPNs), resulting after just a few years in an exceptional amount of new information. One important consequence of those new findings was the modification of the World Health Organization classification and diagnostic algorithms for these diseases, which is still based on the original concept developed by William Dameshek in 1951 and keeps distinct entities under the umbrella of classical Philadelphia-negative MPNs. These MPNs are essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Could a new molecular classification be a better tool to manage MPN patients? Several studies have shown that essential thrombocythemia and primary myelofibrosis can be divided into distinct subtypes based on the presence of the JAK2V617F mutation. Can we now define JAK2-positive diseases to depict a distinct entity from JAK2-negative MPNs? This chapter reviews the significance of JAK2 mutation positivity in the diagnosis, prognosis, and therapy of MPNs.
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Pieri, Lisa, Paola Guglielmelli, and Alessandro Maria Vannucchi. "CHRONIC MYELOPROLIFERATIVE NEOPLASMS: A COLLABORATIVE APPROACH." Mediterranean Journal of Hematology and Infectious Diseases 2, no. 2 (2010): e2010017. http://dx.doi.org/10.4084/mjhid.2010.017.
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The classic chronic myeloproliferative neoplasms (MPN) include different entities that pose significant challenges for their optimal diagnosis, treatment and overall management. Polycythemia Vera and Essential Thrombocythemia are the most common among chronic myeloproliferative neoplasms (MPNs); major causes of morbidity and mortality are represented by arterial and venous thrombosis, as well as evolution to myelofibrosis or transformation to acute leukemia. However, survival is only minimally affected. Therapy aims at reducing the rate of thrombosis without increasing the risk of hematologic transformation which could be caused by exposure to cytotoxic drugs. On the other hand, survival is significantly reduced in primary myelofibrosis, and the clinical manifestations may be disabling. In the absence of therapies with the potential of curing the disease, a careful risk-oriented approach is employed for stratifying patients to the most appropriate, currently available, therapeutic options. In this brief review, we will discuss some of the key issues that can arise along the clinical course of MPNs and require an integrated, strictly patient-oriented, approach.
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Treaba, Diana O., Salwa Khedr, Shamlal Mangray, Cynthia Jackson, Jorge J. Castillo, and Eric S. Winer. "Acute Myeloid Leukemia Evolving from JAK 2-Positive Primary Myelofibrosis and Concomitant CD5-Negative Mantle Cell Lymphoma: A Case Report and Review of the Literature." Case Reports in Hematology 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/875039.
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Primary myelofibrosis (formerly known as chronic idiopathic myelofibrosis), has the lowest incidence amongst the chronic myeloproliferative neoplasms and is characterized by a rather short median survival and a risk of progression to acute myeloid leukemia (AML) noted in a small subset of the cases, usually as a terminal event. As observed with other chronic myeloproliferative neoplasms, the bone marrow biopsy may harbor small lymphoid aggregates, often assumed reactive in nature. In our paper, we present a 70-year-old Caucasian male who was diagnosed with primary myelofibrosis, and after 8 years of followup and therapy developed an AML. The small lymphoid aggregates noted in his bone marrow were neoplastic in nature and represented bone marrow involvement by a CD5-negative mantle cell lymphoma (MCL) that presented without any associated lymphadenopathy. We reviewed the English medical literature to identify a single case report of simultaneous association of AML and a MCL in the bone marrow. The unusual association presented here suggests an increase in observer awareness to apparently benign lymphoid aggregates in chronic myeloproliferative neoplasms.
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Daver, Naval, and Rita Assi. "An Exciting New Era in the Treatment of Myeloproliferative Neoplasms." Oncology & Hematology Review (US) 12, no. 02 (2016): 71. http://dx.doi.org/10.17925/ohr.2016.12.02.71.
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Myeloproliferative neoplasms (MPNs), including primary myelofibrosis and myelofibrosis (MF) evolving from a pre-existing MPN (post polycythemia vera- and post essential thrombocythemia-myelofibrosis) are clonal hematopoietic stem cell disorders with heterogeneous symptoms, mutational profile, transformation risk and prognosis. Given the potentially chronic disease course, the goal of therapy in MF is to alleviate associated signs and symptoms, including reduction in spleen size, weight gain, improved performance status, and control of constitutional symptoms, leading to a prolonged survival and reduced transformation to leukemia.
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Barbui, Tiziano, Guido Finazzi, and Anna Falanga. "Myeloproliferative neoplasms and thrombosis." Blood 122, no. 13 (2013): 2176–84. http://dx.doi.org/10.1182/blood-2013-03-460154.
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Abstract Major causes of morbidity and mortality in myeloproliferative neoplasms are represented by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. The pathogenesis of thrombosis results from a complex interplay of clinical and disease-related factors. Abnormalities of blood cells arising from the clonal proliferation of hematopoietic stem cells involve not only quantitative changes but also qualitative modifications that characterize the switch of these cells from a resting to a procoagulant phenotype. According to age and previous thrombosis, patients are classified in a “high risk” or “low risk”. Novel disease-related determinants such as leukocytosis and JAK2V617F mutational status and/or mutational burden are now under active investigation. In low-risk polycythemia vera patients, only phlebotomy and primary antithrombotic prophylaxis with aspirin is recommended, while in high-risk patients cytotoxic therapy is considered. Whether novel drugs targeting the constitutively active JAK2/STAT pathway will improve the management of thrombosis is a challenge for future studies.
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Ristic, Slobodan, Milica Radojkovic, Tatjana Kostic, Vesna Spasovski, Sonja Pavlovic, and Vesna Cemerikic-Martinovic. "JAK2V617F mutation in a patient with B-cell chronic lymphocytic leukemia and prefibrotic primary myelofibrosis." Srpski arhiv za celokupno lekarstvo 143, no. 11-12 (2015): 739–43. http://dx.doi.org/10.2298/sarh1512739r.
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Introduction. Secondary malignancies, particularly solid tumors, are common in patients with chronic lymphocytic leukemia (CLL), but association of myeloproliferative neoplasms and chronic lymphocytic leukemia in the same patient is very rare. Case Outline. We report of a 67-year-old man with B-cell chronic lymphoid leukemia (B-CLL) who developed primary myelofibrosis (PMF) nine years after initial diagnosis. Patient received alkylation agents and purine analogue, which can be a predisposing factor for the development of myeloproliferative neoplasms. JAK2V617F mutation was not present initially at the time of CLL diagnosis, but was found after nine years when PMF occurred, which indicates that B-CLL and PMF represent two separate clonal origin neoplasms. Conclusion. Pathogenic mechanisms for the development of myeloproliferative and lymphoproliferative neoplasms in the same patient are unknown. Further research is needed to determine whether these malignancies originate from two different cell clones or arise from the same pluripotent hematopoietic stem cell.
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McMullin, Mary Frances, and Lesley Ann Anderson. "Aetiology of Myeloproliferative Neoplasms." Cancers 12, no. 7 (2020): 1810. http://dx.doi.org/10.3390/cancers12071810.
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Myeloproliferative neoplasms (MPNs) have estimated annual incidence rates for polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis of 0.84, 1.03, and 0.47 per 100,000. Prevalence is much higher, particularly for PV and ET, as mortality rates are relatively low. Patients are often concerned about why they developed an MPN and epidemiological studies enable the identification of potential causative factors. Previous work in small heterogeneous studies has identified a variety of risk factors associated with MPNs including family history of MPN, autoimmune conditions, some occupational exposures, and blood donation. At a population level, germline predisposition factors in various populations have been associated with MPNs. The pilot MOSAICC (Myeloproliferative Neoplasm: An In-depth Case-Control) study is one of the largest epidemiological studies in MPN ever carried out to date. It demonstrated the most effective methods for carrying out a significant epidemiological study in this patient group including the best way of recruiting controls, as well as how to evaluate occupational and lifestyle exposures, evaluate symptoms, and collect biological samples. Significant results linked to MPNs in the pilot study of 106 patients included smoking, obesity, and childhood socioeconomic status. The methodology is now in place for a much larger ongoing MOSAICC study which should provide further insight into the potential causes of MPNs.
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Ryabukhina, Yu E., P. A. Zeynalova, O. I. Timofeeva, et al. "Combination approach to diagnosis and treatment of an elderly patient with chronic Ph-negative myeloproliferative neoplasm and concomitant surgical pathology. Clinical observation." MD-Onco 1, no. 1 (2021): 61–65. http://dx.doi.org/10.17650/2782-3202-2021-1-1-61-65.
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Chronic myeloproliferative neoplasms (CMPN), Ph-negative, are of clonal nature, develop on the level of hematopoietic stem cell and are characterized by proliferation of one or more hematopoietic pathways. Currently, the group of Ph-negative CMPN includes essential thrombocythemia, primary myelofibrosis, polycythemia vera, myeloproliferative neoplasm unclassifiable.Identification of mutations in the Jak2 (V617F), CALR, and MPL genes extended understanding of biological features of Ph-negative CMPN and improved differential diagnosis of myeloid neoplasms. Nonetheless, clinical practice still encounters difficulties in clear separation between such disorders as primary myelofibrosis, early-stage and transformation of essential thrombocythemia into myelofibrosis with high thrombocytosis. Thrombocytosis is one of the main risk factors for thromboembolic complications, especially in elderly people.A clinical case of an elderly patient with fracture of the left femur developed in the context of Ph-negative CMPN (myelofibrosis) with high level of thrombocytosis is presented which in combination with enforced long-term immobilization and presence of additional risk created danger of thrombosis and hemorrhage during surgery and in the postoperative period.
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Melikyan, Anait L., Irina N. Subortseva, Elena A. Gilyazitdinova, et al. "Thrombosis in patients with myeloproliferative neoplasms. Case report." Terapevticheskii arkhiv 93, no. 7 (2021): 800–804. http://dx.doi.org/10.26442/00403660.2021.07.200925.
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Thrombotic complications are the most significant factors determining the prognosis in myeloproliferative neoplasms. Markers for assessing the risk of thrombosis are the number of leukocytes, platelets, hemoglobin level, hematocrit, age, molecular status, history of thrombosis, obesity, arterial hypertension, hyperlipidemia, hereditary or acquired thrombophilia. The pathogenesis of thrombosis in patients with myeloproliferative neoplasms is complex and multifactorial. In most cases, the etiological factor remains unknown. Currently, antiplatelet and anticoagulant therapy is carried out on an individual basis. The algorithm for primary and secondary (after thrombosis) prevention requires development and testing. We present a clinical case of repeated arterial and venous thrombotic complications in a patient with primary myelofibrosis.
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Cazzola, Mario, and Robert Kralovics. "From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms." Blood 123, no. 24 (2014): 3714–19. http://dx.doi.org/10.1182/blood-2014-03-530865.
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Abstract Our understanding of the genetic basis of myeloproliferative neoplasms began in 2005, when the JAK2 (V617F) mutation was identified in polycythemia vera, essential thrombocythemia, and primary myelofibrosis. JAK2 exon 12 and MPL exon 10 mutations were then detected in subsets of patients, and subclonal driver mutations in other genes were found to be associated with disease progression. Recently, somatic mutations in the gene CALR, encoding calreticulin, have been found in most patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 and MPL. The JAK-STAT pathway appears to be activated in all myeloproliferative neoplasms, regardless of founding driver mutations. These latter, however, have different effects on clinical course and outcomes. Thus, evaluation of JAK2, MPL, and CALR mutation status is important not only for diagnosis but also for prognostication. These genetic data should now also be considered in designing clinical trials.
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Lanikova, Lucie, Olga Babosova, and Josef T. Prchal. "Experimental Modeling of Myeloproliferative Neoplasms." Genes 10, no. 10 (2019): 813. http://dx.doi.org/10.3390/genes10100813.
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Myeloproliferative neoplasms (MPN) are genetically very complex and heterogeneous diseases in which the acquisition of a somatic driver mutation triggers three main myeloid cytokine receptors, and phenotypically expresses as polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The course of the diseases may be influenced by germline predispositions, modifying mutations, their order of acquisition and environmental factors such as aging and inflammation. Deciphering these contributory elements, their mutual interrelationships, and their contribution to MPN pathogenesis brings important insights into the diseases. Animal models (mainly mouse and zebrafish) have already significantly contributed to understanding the role of several acquired and germline mutations in MPN oncogenic signaling. Novel technologies such as induced pluripotent stem cells (iPSCs) and precise genome editing (using CRISPR/Cas9) contribute to the emerging understanding of MPN pathogenesis and clonal architecture, and form a convenient platform for evaluating drug efficacy. In this overview, the genetic landscape of MPN is briefly described, with an attempt to cover the main discoveries of the last 15 years. Mouse and zebrafish models of the driver mutations are discussed and followed by a review of recent progress in modeling MPN with patient-derived iPSCs and CRISPR/Cas9 gene editing.
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Taj, Sadia, Mona Aziz, Maliha Asif, Amna Arooj, Madiha Islam, and Adnan Tariq. "Coagulation profile in myeloproliferative Neoplasms." Professional Medical Journal 27, no. 05 (2020): 944–49. http://dx.doi.org/10.29309/tpmj/2020.27.05.3864.
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Objectives: Evaluation of coagulation profile in patients with Myeloproliferative Neoplasms. Study Design: Cross sectional survey. Setting: Department of Haematology, Shaikh Zayed Hospital, Lahore. Period: From 10-03-2015 to 09-03-2016. Materials & Methods: A total of 55 patients of myeloproliferative neoplasms (Chronic Myeloid leukaemia, Polycythemia vera, Essential thrombocytosis and Primary Myelofibrosis) were studied over 1 year period. Patients of >15 yrs and both the genders were included. Patients already on anticoagulation and liver disease were excluded. All patients underwent screening of PT, APTT and D-dimer. PT and APTT was measured by KC4 Amelung coagulometer and D-Dimer by Latex Kit 60X. Results: Twenty four of 55 cases (43.64%) of myeloproliferative neoplasms had elevated Prothrombin time. Activated partial thromboplastin time was elevated in 18 of 55 (32.73%) cases and D-Dimer was elevated in 11 of 55 (20%) cases. Conclusion: CML is statistically the most spreading form of MPN and ET is least common form in comparison with other MPNs. Thrombohaemorrhagic complications significantly affect the morbidity and mortality of MPN patients which can be assessed by coagulation studies. Timely diagnosis of these prothrombotic/haemorrhagic states can decrease the morbidity in these patients
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Tamari, Roni, and Hugo Castro-Malaspina. "Allogeneic haematopoietic stem cell transplantation for primary myelofibrosis and myelofibrosis evolved from other myeloproliferative neoplasms." Current Opinion in Hematology 22, no. 2 (2015): 184–90. http://dx.doi.org/10.1097/moh.0000000000000121.
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Hobbs, Gabriela, Cansu Cimen Bozkus, Erin Moshier, et al. "PD-1 inhibition in advanced myeloproliferative neoplasms." Blood Advances 5, no. 23 (2021): 5086–97. http://dx.doi.org/10.1182/bloodadvances.2021005491.
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Abstract Myelofibrosis (MF) is a clonal stem cell neoplasm characterized by abnormal JAK-STAT signaling, chronic inflammation, cytopenias, and risk of transformation to acute leukemia. Despite improvements in the therapeutic options for patients with MF, allogeneic hematopoietic stem cell transplantation remains the only curative treatment. We previously demonstrated multiple immunosuppressive mechanisms in patients with MF, including increased expression of programmed cell death protein 1 (PD-1) on T cells compared with healthy controls. Therefore, we conducted a multicenter, open-label, phase 2, single-arm study of pembrolizumab in patients with Dynamic International Prognostic Scoring System category of intermediate-2 or greater primary, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. The study followed a Simon 2-stage design and enrolled a total of 10 patients, 5 of whom had JAK2V617mutation, 2 had CALR mutation, and 6 had additional mutations. Most patients were previously treated with ruxolitinib. Pembrolizumab treatment was well tolerated, but there were no objective clinical responses, so the study closed after the first stage was completed. However, immune profiling by flow cytometry, T-cell receptor sequencing, and plasma proteomics demonstrated changes in the immune milieu of patients, which suggested improved T-cell responses that can potentially favor antitumor immunity. The fact that these changes were not reflected in a clinical response strongly suggests that combination immunotherapeutic approaches rather than monotherapy may be necessary to reverse the multifactorial mechanisms of immune suppression in myeloproliferative neoplasms. This trial was registered at www.clinicaltrials.gov as #NCT03065400.
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Korsakova, N. E. "Endothelium state in Ph-negative myeloproliferative neoplasms." Сибирский научный медицинский журнал 41, no. 6 (2021): 30–44. http://dx.doi.org/10.18699/ssmj20210603.
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Thrombotic complications contribute significantly in morbidity and mortality of patients with Ph-negative myeloproliferative neoplasms (MPN) including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Vascular endothelium is essential component of hemostatic system, and its functionality failure plays important role in prothrombotic states development. This review comprises analysis of available data on assessment of endothelium state characteristics in Ph-negative MPN and their detection with different methods. The search of literature sources was carried out using PubMed and eLibrary databases. The analysis of research results obtained with the use of different estimation techniques indicates that patients with Ph-negative MPN are characterized by endothelium activation, damage, and, consequently, dysfunction. Endothelium abnormalities associated with myeloproliferation have an effect on all endothelial functions fulfillment. Endothelial dysfunction represents important component of thrombosis pathogenesis in Ph-negative MPN.
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Prakash, Sonam, and Attilio Orazi. "How I Diagnose Primary Myelofibrosis." American Journal of Clinical Pathology 157, no. 4 (2022): 518–30. http://dx.doi.org/10.1093/ajcp/aqac016.
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Abstract Objectives Primary myelofibrosis (PMF) is a BCR/ABL1-negative myeloproliferative neoplasm (MPN) with a shorter overall survival and a higher leukemic transformation than other BCR/ABL1-negative MPNs. Diagnosis of PMF can be challenging given its clinical, morphologic, molecular overlap with other myeloid neoplasms also associated with myelofibrosis, and reactive conditions. Methods We summarize and discuss the clinical, morphologic, and molecular features useful for diagnosing PMF as well as salient features helpful in distinguishing PMF from myelodysplastic syndrome with associated fibrosis and autoimmune myelofibrosis using a case-based approach. Results PMF in both its prefibrotic and fibrotic stages, the latter characterized by reticulin/collagen marrow fibrosis, is characterized by a proliferation of predominantly abnormal megakaryocytes and granulocytes in the bone marrow. Driver mutations in JAK2, CALR, or MPLare seen in approximately 90% of PMF cases. In triple-negative cases, the presence of cytogenetic abnormalities and other somatic mutations identified by next-generation sequencing can help establish a diagnosis of PMF in the appropriate clinical and morphologic context. Conclusions Given the significant difference in prognosis and treatment, integration of clinical, morphological, and molecular/genetic findings is essential in distinguishing PMF from other etiologies that can demonstrate myelofibrosis.
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Rumi, Elisa, and Mario Cazzola. "Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms." Blood 129, no. 6 (2017): 680–92. http://dx.doi.org/10.1182/blood-2016-10-695957.
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Abstract Philadelphia-negative classical myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 revision of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues includes new criteria for the diagnosis of these disorders. Somatic mutations in the 3 driver genes, that is, JAK2, CALR, and MPL, represent major diagnostic criteria in combination with hematologic and morphological abnormalities. PV is characterized by erythrocytosis with suppressed endogenous erythropoietin production, bone marrow panmyelosis, and JAK2 mutation. Thrombocytosis, bone marrow megakaryocytic proliferation, and presence of JAK2, CALR, or MPL mutation are the main diagnostic criteria for ET. PMF is characterized by bone marrow megakaryocytic proliferation, reticulin and/or collagen fibrosis, and presence of JAK2, CALR, or MPL mutation. Prefibrotic myelofibrosis represents an early phase of myelofibrosis, and is characterized by granulocytic/megakaryocytic proliferation and lack of reticulin fibrosis in the bone marrow. The genomic landscape of MPNs is more complex than initially thought and involves several mutant genes beyond the 3 drivers. Comutated, myeloid tumor-suppressor genes contribute to phenotypic variability, phenotypic shifts, and progression to more aggressive disorders. Patients with myeloid neoplasms are at variable risk of vascular complications, including arterial or venous thrombosis and bleeding. Current prognostic models are mainly based on clinical and hematologic parameters, but innovative models that include genetic data are being developed for both clinical and trial settings. In perspective, molecular profiling of MPNs might also allow for accurate evaluation and monitoring of response to innovative drugs that target the mutant clone.
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Gul, Ayesha, Sheeba Ishtiaq, Hina Umair, and Memoona Rasheed. "Frequency of JAK2 and MPL Mutation in BCR/ABL Negative Myelofibrosis in KPK." Journal of Rawalpindi Medical College 26, no. 2 (2022): 266–70. http://dx.doi.org/10.37939/jrmc.v26i2.1845.
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Introduction: BCR-ABL1-negative myeloproliferative disorders are a sub-group of myeloproliferative neoplasms (MPNs) that consist of polycythemia Vera (PV), Essential thrombocythemia (ET) and Primary Myelofibrosis (PMF). Over the past decade, the morphological and clinical division of myeloproliferative neoplasms (MPN) has changed to a classification that describes the molecular heterogeneity and is unique to this subgroup of haematological malignancies. This includes alterations in Janus kinase 2 (JAK2), and MPL genes. Objective: To determine the frequency of JAK2 (p.V617F) and MPL (p.W515L) mutation in primary myelofibrosis in KPK province of Pakistan. Materials and Methods: Fifty patients with PMF were enrolled in the study. JAK2 mutation status was determined using allele specific primers and MPL mutation was detected by direct Sanger sequencing technique. The data was analyzed using BioEdit by aligning the sequence data with reference genome hg19 assembly. Results: Among 50 patients, 41 patients were diagnosed with PMF, while 9 patients had secondary myelofibrosis i.e. Post PV-MF and Post ET-MF. Out of the 41 PMF patient 2 patients had MPL gene variation, while one of the Post ET –MF had a MPL gene variation. Forty eight (96%) were positive for JAK2 mutation. Five patients who had MPL mutation also showed JAK 2 mutation. Two of the MPL positive patients were also positive for JAK2 mutation. Conclusion: We reported rate of recurrence of JAK2 mutation in 96% of the cases and MPL exon 10 mutations in 6% of the cases.
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Toros, Ahmet Burak, Serkan Gokcay, Guven Cetin, Muhlis Cem Ar, Yesim Karagoz, and Besir Kesici. "Portal Hypertension and Myeloproliferative Neoplasms: A Relationship Revealed." ISRN Hematology 2013 (September 16, 2013): 1–5. http://dx.doi.org/10.1155/2013/673781.
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Background/Objectives. Patients with myeloproliferative neoplasms have a well-established increased risk of thrombosis. Many trials report identification of an underlying myeloproliferative neoplasm by investigation of the patients developing portal hypertensive esophagus and/or fundus variceal hemorrhage in the absence of any known etiology. This trial was designed to investigate the association between myeloproliferative neoplasms and portal hypertension and to detect the frequency of portal hypertension development in this subset of patients. Methodology. Twenty-nine patients previously diagnosed with polycythemia vera, essential thrombocytopenia, and primary myelofibrosis, who were under followup at the hematology outpatient clinic of our hospital, were included in the trial. Results. In our trial, we detected portal hypertension in 13.8% of the patients (n=4), as a finding that was similar to those obtained in other studies performed to date. Conclusions. Considering the fact that diagnosis of myeloproliferative neoplasms usually takes a long time, treatment should be started (while, on the other hand, assessing the investigational and therapeutical choices for the complications) right after the bone marrow biopsy or cytogenetic studies required for establishing the final diagnosis have been performed.
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Koschmieder, Steffen. "How I Manage Thrombotic/Thromboembolic Complications in Myeloproliferative Neoplasms." Hämostaseologie 40, no. 01 (2020): 047–53. http://dx.doi.org/10.1055/s-0040-1701474.
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AbstractPatients with myeloproliferative neoplasms (MPNs), such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are at increased risk for arterial and venous thrombosis/thromboembolism. In particular, the risk of splanchnic venous thrombosis, such as portal vein thrombosis or Budd–Chiari syndrome, is significantly higher in patients with MPN than in the normal population. At the same time, MPN patients are at increased risk for severe bleeding. Therefore, the treatment of patients with MPN must be based on their suspected probability of thrombosis/thromboembolism and bleeding. For this purpose, patient and MPN-specific risk factors are used. Patients at expected high risk of thrombosis should receive adequate primary or secondary thromboprophylaxis in addition to cytoreductive therapy. This may consist of antiplatelet agents and/or anticoagulant agents and must be balanced with the individual bleeding risk. The goal is to increase the quality of life and life span of patients with MPNs by preventing (re-)thrombosis and severe bleeding.
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Keechilat, Pavithran, and Shripad Brahmanand Pande. "Janus kinase inhibitors: jackpot or potluck?" Oncology Reviews 6, no. 1 (2012): 13. http://dx.doi.org/10.4081/oncol.2012.e13.
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The reports of a unique mutation in the Janus kinase-2 gene (<em>JAK2</em>) in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN): primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.
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Torres, Dania G., Jhemerson Paes, Allyson G. da Costa, et al. "JAK2 Variant Signaling: Genetic, Hematologic and Immune Implication in Chronic Myeloproliferative Neoplasms." Biomolecules 12, no. 2 (2022): 291. http://dx.doi.org/10.3390/biom12020291.
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The JAK2V617F variant constitutes a genetic alteration of higher frequency in BCR/ABL1 negative chronic myeloproliferative neoplasms, which is caused by a substitution of a G ˃ T at position 1849 and results in the substitution of valine with phenylalanine at codon 617 of the polypeptide chain. Clinical, morphological and molecular genetic features define the diagnosis criteria of polycythemia vera, essential thrombocythemia and primary myelofibrosis. Currently, JAK2V617F is associated with clonal hematopoiesis, genomic instability, dysregulations in hemostasis and immune response. JAK2V617F clones induce an inflammatory immune response and lead to a process of immunothrombosis. Recent research has shown great interest in trying to understand the mechanisms associated with JAK2V617F signaling and activation of cellular and molecular responses that progressively contribute to the development of inflammatory and vascular conditions in association with chronic myeloproliferative neoplasms. Thus, the aim of this review is to describe the main genetic, hematological and immunological findings that are linked to JAK2 variant signaling in chronic myeloproliferative neoplasms.
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P. Hasserjian, Robert. "Myeloproliferative Neoplasms Including Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis, Chronic Neutrophilic Leukemia, and Myeloproliferative Neoplasm, Unclassifiable." Current Cancer Therapy Reviews 8, no. 1 (2012): 14–29. http://dx.doi.org/10.2174/157339412799462495.
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Simon, Zsófia, Imelda Marton, Zita Borbényi, and Árpád Illés. "Aktualitások a primer myelofibrosis ellátásában." Orvosi Hetilap 157, no. 39 (2016): 1547–56. http://dx.doi.org/10.1556/650.2016.30531.
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Primary myelofibrosis is one of the Philadelphia negative chronic myeloproliferative neoplasms. It is a rare disease featured by cytopenias and hepatosplenomegaly. Although the etiology of the disease is still unknown, our knowledge about its pathology and prognosis has been improving in the last few years. Furthermore, the JAK2 inhibitor ruxolitinib has become available in Hungary since 2015. Beside its high efficacy in spleen volume and in reduction of myelofibrosis-associated symptoms, this novel therapy also exerts a disease-modifying effect and, therefore, ruxolitinib may improve the life expectancy too. Treatment approach of myelofibrosis has been changed these years, which gives a reason for this summary. Orv. Hetil., 2016, 157(39), 1547–1556.
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Langabeer, Stephen E., James Nolan, Karl Haslam, Lindsey Clarke, Richard Flavin, and Eibhlin Conneally. "Evading Capture by Residual Disease Monitoring: Extramedullary Manifestation ofJAK2V617F-Positive Primary Myelofibrosis After Allogeneic Stem Cell Transplantation." Case Reports in Hematology 2015 (2015): 1–4. http://dx.doi.org/10.1155/2015/703457.
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Monitoring of theJAK2V617F allele burden in myeloproliferative neoplasms after allogeneic stem cell transplantation is useful to determine levels of residual disease and has the potential to detect early relapse and guide subsequent clinical intervention. A case is described of aJAK2V617F-positive primary myelofibrosis patient who underwent allogeneic stem cell transplantation. Prospective residual disease monitoring of the peripheral blood failed to detect an extramedullary manifestation of the disease, a periorbital myeloid sarcoma, arising nearly three years after transplant. This case serves to highlight a pitfall in residual disease monitoring for myeloproliferative neoplasm-associated mutations in the post-allogeneic stem cell transplantation setting.
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Arachchillage, Deepa RJ, and Mike Laffan. "Pathogenesis and Management of Thrombotic Disease in Myeloproliferative Neoplasms." Seminars in Thrombosis and Hemostasis 45, no. 06 (2019): 604–11. http://dx.doi.org/10.1055/s-0039-1693477.
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AbstractChronic myeloproliferative neoplasms (MPN) are characterized by clonal expansion of an abnormal hematopoietic stem/progenitor cell and include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Venous thrombosis, often at unusual sites, including splanchnic vein thrombosis and arterial thrombosis, as well as a hemorrhagic tendency and a propensity to transform into myelofibrosis or acute leukemia are common complications in patients with MPNs. The pathogenesis of thrombosis in MPN patients is complex and multifactorial. Disease related factors, such as an increase in blood cell counts (i.e., leukocytosis, erythrocytosis, and thrombocytosis), and more importantly presence of JAK2 mutation can interact with non-disease patient related factors such as age, previous history of thrombotic events, obesity, hypertension, hyperlipidemia, and presence of thrombophilic defects. The overall rate of recurrent thrombosis after venous thromboembolism (VTE) is 6.0 to 6.5 per 100 patient-years in patients with MPN compared to 2.7 to 3.7 per 100 patient-years in patients without MPN, and antithrombotic therapy with vitamin K antagonists (VKAs) is associated with a clear benefit, reducing the incidence of recurrence by 48 to 69%. Life-long oral anticoagulation with VKAs is the cornerstone of the antithrombotic treatment for splanchnic vein thrombosis (SVT). Patients with MPN-related cerebral venous thrombosis (CVT) should also be treated with long-term anticoagulation with VKAs. The role of direct acting oral anticoagulants in patients with thrombosis and MPN is not established and the use of these anticoagulants should be considered on an individual basis according to the risk of recurrent of VTE and bleeding.
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Iurlo, Alessandra, Daniele Cattaneo, and Umberto Gianelli. "Blast Transformation in Myeloproliferative Neoplasms: Risk Factors, Biological Findings, and Targeted Therapeutic Options." International Journal of Molecular Sciences 20, no. 8 (2019): 1839. http://dx.doi.org/10.3390/ijms20081839.
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Myeloproliferative neoplasms represent a heterogenous group of disorders of the hematopoietic stem cell, with an intrinsic risk of evolution into acute myeloid leukemia. The frequency of leukemic evolution varies according to myeloproliferative neoplasms subtype. It is highest in primary myelofibrosis, where it is estimated to be approximately 10–20% at 10 years, following by polycythemia vera, with a risk of 2.3% at 10 years and 7.9% at 20 years. In essential thrombocythemia, however, transformation to acute myeloid leukemia is considered relatively uncommon. Different factors are associated with leukemic evolution in myeloproliferative neoplasms, but generally include advanced age, leukocytosis, exposure to myelosuppressive therapy, cytogenetic abnormalities, as well as increased number of mutations in genes associated with myeloid neoplasms. The prognosis of these patients is dismal, with a medium overall survival ranging from 2.6–7.0 months. Currently, there is no standard of care for managing the blast phase of these diseases, and no treatment to date has consistently led to prolonged survival and/or hematological remission apart from an allogeneic stem cell transplant. Nevertheless, new targeted agents are currently under development. In this review, we present the current evidence regarding risk factors, molecular characterization, and treatment options for this critical subset of myeloproliferative neoplasms patients.
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Atere, Muhammed, Rana Al-Zakhari, Jennifer Collins, Francesco Rotatori, and Lloyd Muzangwa. "Atypical Myocardial Infarction with Apical Thrombus and Systemic Embolism: A Rare Presentation of Likely JAK2 V617F-Positive Myeloproliferative Neoplasm." Case Reports in Oncological Medicine 2020 (May 19, 2020): 1–4. http://dx.doi.org/10.1155/2020/9654048.
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A few types of myeloproliferative neoplasms may be significant for Janus-associated kinase 2 mutation, JAK2 V617F, including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The prevalence of JAK2 mutation is low in the general population but higher in patients with myeloproliferative neoplasms. Some patients with JAK2 V617F-positive essential thrombocythemia are asymptomatic, but others may develop hemorrhagic or thromboembolic complications. Thromboembolism may occur in vessels of high flow organs like the heart and, thereby, present as myocardial infarction. Nonetheless, these patients are usually symptomatic with complaints of chest pain, for example. Atypical (asymptomatic) myocardial infarction with mild thrombocytosis may be the first clue for possible essential thrombocythemia with JAK2 V617F. In this report, we discuss a case of atypical (asymptomatic) myocardial infarction with secondary thromboembolism in a patient positive for JAK2 V617F with a likely myeloproliferative neoplasm.
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Sghibneva-Bobeico, Nina, Vasile Musteata, Maria Robu, et al. "Clinical patterns and complete blood count parameters in the young patients with primary myelofibrosis in the prefibrotic stage." Moldovan Journal of Health Sciences, no. 4 (December 2022): 22–26. http://dx.doi.org/10.52645/mjhs.2022.4.04.
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Introduction. Primary myelofibrosis is a rare myeloproliferative neoplasm that affects 0.2-1.5 people per 100,000. As a rule, the diagnosis is confirmed after 60 years, but recently, hematologists around the world have encountered the problem of primary myelofibrosis in young people. The classic manifestations of myelofibrosis are characterized by splenomegaly, cytopenia, and bone marrow fibrosis, but in patients younger than 40 years, the diagnosis is most often made in the prefibrotic stage of the neoplasm. The aim of the paper is to identify and evaluate the clinical and hematological features of primary myelofibrosis in young patients in the prefibrotic stage. Material and methods. A retrospective study was performed on clinical cases of primary myelofibrosis, registered at the Oncological Institute of the Republic of Moldova. The diagnosis was confirmed according to 2016 WHO criteria based on histological and molecular studies. We enrolled young patients under the age of 40 who had been diagnosed with prefibrosis in our study and analyzed them for clinical manifestations and complete blood count parameters. To optimize the analysis, all patients were divided into two groups according to their age: 18–29 and 30–40 years old. Results. Changes in the complete blood count, manifested by thrombocytosis and leukocytosis, are the main laboratory patterns of primary myelofibrosis in young patients in the prefibrotic stage. The most relevant clinical features are splenomegaly and hepatomegaly, but no correlation between these manifestations has been found. Conclusions. The classical clinical and hematological characteristics of primary myelofibrosis do not specify lowand intermediate-risk patients’ management in the prefibrotic stage, as compared with the other chronic myeloproliferative BCR-ABL-negative neoplasms. The proliferation type of primary myelofibrosis is characteristic for young patients with pre-fibrotic stage. According to our results, the main manifestations in the prefibrotic stage are detected in a complete blood count and comprise anemia, leucopenia, leukocytosis, and thrombocytosis.
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Belčič Mikič, Tanja, Tadej Pajič, Samo Zver, and Matjaž Sever. "The Contemporary Approach to CALR-Positive Myeloproliferative Neoplasms." International Journal of Molecular Sciences 22, no. 7 (2021): 3371. http://dx.doi.org/10.3390/ijms22073371.
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CALR mutations are a revolutionary discovery and represent an important hallmark of myeloproliferative neoplasms (MPN), especially essential thrombocythemia and primary myelofibrosis. To date, several CALR mutations were identified, with only frameshift mutations linked to the diseased phenotype. It is of diagnostic and prognostic importance to properly define the type of CALR mutation and subclassify it according to its structural similarities to the classical mutations, a 52-bp deletion (type 1 mutation) and a 5-bp insertion (type 2 mutation), using a statistical approximation algorithm (AGADIR). Today, the knowledge on the pathogenesis of CALR-positive MPN is expanding and several cellular mechanisms have been recognized that finally cause a clonal hematopoietic expansion. In this review, we discuss the current basis of the cellular effects of CALR mutants and the understanding of its implementation in the current diagnostic laboratorial and medical practice. Different methods of CALR detection are explained and a diagnostic algorithm is shown that aids in the approach to CALR-positive MPN. Finally, contemporary methods joining artificial intelligence in accordance with molecular-genetic biomarkers in the approach to MPN are presented.
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Vargas-Viveros, Pablo, Rafael Hurtado Monroy, and Myrna Candelaria-Hernandez. "Significant Improvement In Quality Of Life (QoL) In Patients With Chronic Myeloproliferative Neoplasms and Myelofibrosis Treated With JAK-1 and JAK-2 Inhibitor Ruxolitinib. A Single Institution Experience In Mexico." Blood 122, no. 21 (2013): 5252. http://dx.doi.org/10.1182/blood.v122.21.5252.5252.
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Abstract Introduction Myeloproliferative Neoplasms can shorten the life of patients and affect severely their quality of life as a result of constitutional symptoms mediated by cytokines and from massive splenomegaly characteristic of these diseases. The objective measurement of symptoms in Myelofibrosis is essential for the presence of general constitutional symptoms as fatigue and is considered adverse prognostic value for survival. The systematic measurement of symptoms in Myelofibrosis is essential for assessing the outcome of treatment with JAK-2 inhibitors. Material and Methods To assess the impact on quality of life in patients with Myeloproliferative Neoplasms treated with the inhibitor Ruxolitinib, there was applied the questionnaire Myelofibrosis Symptom Assessment Form (Mesa et al. Leukemia Research. 2009: 33; 1199-1203) to 16 patients included in the Compassionate Use of Ruxolitinib Program: 8 men and 8 women were included with a median age of 63 years; 4 patients with primary Myelofibrosis, 3 with Myelofibrosis post Polycitemia vera and 9 with Myelofibrosis post essential Thrombocythemia. The median patient follow-up was 9 months. The patients started with a dose of 20 mg Ruxolitinib orally every 12 hours. Results The questionnaire was administered to all patients at each visit and the results of the ratings of the patients were presented as median of each answer at baseline, 3, 6 and 12 months of follow-up (table 1). By comparing the differences of each parameter measured between the start and at 3, 6 and 12 months were statistically significant for all variables (P <0.001, CI: 95%). The most significant changes were observed when comparing data at baseline and follow-up to the maximum time, however were obvious from the first quarter of observation on fatigue and symptoms dependent splenomegaly in most general symptoms, which actually disappeared completely after 3 months of treatment and not relapsed during the track and in the perception of the quality of life of patients. The variables with lower proportional change recorded were general activity, mood, walking tolerance and everyday work. Discussion and conclusions The treatment of Myeloproliferative Neoplasms with Ruxolitinib represents a major advance in the management of malignant Myeloproliferative and achieved excellent improvement in overall constitutional symptom control, splenomegaly and the general perception of the quality of life of these patients. The objective measurement of symptoms of Myelofibrosis is essential, since the presence of general constitutional symptoms as fatigue is considered adverse prognostic value for survival and systematic measurement of symptoms in Myelofibrosis is essential for assessing the outcome of treatment with inhibitors JAK-2. Disclosures: No relevant conflicts of interest to declare.
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Koschmieder, Steffen. "The Approach to Thrombosis Prevention across the Spectrum of Philadelphia-Negative Classic Myeloproliferative Neoplasms." Hemato 2, no. 3 (2021): 392–402. http://dx.doi.org/10.3390/hemato2030025.
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Patients with myeloproliferative neoplasm (MPN) are potentially facing diminished life expectancy and decreased quality of life, due to thromboembolic and hemorrhagic complications, progression to myelofibrosis or acute leukemia with ensuing signs of hematopoietic insufficiency, and disturbing symptoms such as pruritus, night sweats, and bone pain. In patients with essential thrombocythemia (ET) or polycythemia vera (PV), current guidelines recommend both primary and secondary measures to prevent thrombosis. These include acetylsalicylic acid (ASA) for patients with intermediate- or high-risk ET and all patients with PV, unless they have contraindications for ASA use, and phlebotomy for all PV patients. A target hematocrit level below 45% is demonstrated to be associated with decreased cardiovascular events in PV. In addition, cytoreductive therapy is shown to reduce the rate of thrombotic complications in high-risk ET and high-risk PV patients. In patients with prefibrotic primary myelofibrosis (pre-PMF), similar measures are recommended as in those with ET. Patients with overt PMF may be at increased risk of bleeding and thus require a more individualized approach to thrombosis prevention. This review summarizes the thrombotic risk factors and primary and secondary preventive measures against thrombosis in MPN.
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Dasanu, Constantin A. "Erythematous skin lesions with necrotic centers on lower extremities due to the use of ruxolitinib for primary myelofibrosis." Journal of Oncology Pharmacy Practice 25, no. 4 (2018): 990–92. http://dx.doi.org/10.1177/1078155218768875.
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Ruxolitinib is a small molecule JAK-2 inhibitor approved for the treatment of certain myeloproliferative neoplasms. Ruxolitinib-related skin toxicity is extremely rare. We report herein an unusual erythematous skin eruption with necrotic centers involving lower extremities in a patient with primary myelofibrosis treated with ruxolitinib. Awareness of this unusual skin toxicity with ruxolitinib becomes even more important as JAK-2 inhibition might soon find clinical applications in dermatology.
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Rumi, Elisa, Chiara Trotti, Daniele Vanni, Ilaria Carola Casetti, Daniela Pietra, and Emanuela Sant’Antonio. "The Genetic Basis of Primary Myelofibrosis and Its Clinical Relevance." International Journal of Molecular Sciences 21, no. 23 (2020): 8885. http://dx.doi.org/10.3390/ijms21238885.
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Among classical BCR-ABL-negative myeloproliferative neoplasms (MPN), primary myelofibrosis (PMF) is the most aggressive subtype from a clinical standpoint, posing a great challenge to clinicians. Whilst the biological consequences of the three MPN driver gene mutations (JAK2, CALR, and MPL) have been well described, recent data has shed light on the complex and dynamic structure of PMF, that involves competing disease subclones, sequentially acquired genomic events, mostly in genes that are recurrently mutated in several myeloid neoplasms and in clonal hematopoiesis, and biological interactions between clonal hematopoietic stem cells and abnormal bone marrow niches. These observations may contribute to explain the wide heterogeneity in patients’ clinical presentation and prognosis, and support the recent effort to include molecular information in prognostic scoring systems used for therapeutic decision-making, leading to promising clinical translation. In this review, we aim to address the topic of PMF molecular genetics, focusing on four questions: (1) what is the role of mutations on disease pathogenesis? (2) what is their impact on patients’ clinical phenotype? (3) how do we integrate gene mutations in the risk stratification process? (4) how do we take advantage of molecular genetics when it comes to treatment decisions?
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Saint-Martin, Cécile, Gwendoline Leroy, François Delhommeau, et al. "Analysis of the Ten-Eleven Translocation 2 (TET2) gene in familial myeloproliferative neoplasms." Blood 114, no. 8 (2009): 1628–32. http://dx.doi.org/10.1182/blood-2009-01-197525.
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Abstract The JAK2V617F mutation does not elucidate the phenotypic variability observed in myeloproliferative neoplasm (MPN) families. A putative tumor suppressor gene, TET2, was recently implicated in MPN and myelodysplastic syndromes through the identification of acquired mutations affecting hematopoietic stem cells. The present study analyzed the TET2 gene in 61 MPN cases from 42 families. Fifteen distinct mutations were identified in 12 (20%) JAK2V617F-positive or -negative patients. In a patient with 2 TET2 mutations, the analysis of 5 blood samples at different phases of her disease showed the sequential occurrence of JAK2V617F and TET2 mutations concomitantly to the disease evolution. Analysis of familial segregation confirmed that TET2 mutations were not inherited but somatically acquired. TET2 mutations were mainly observed (10 of 12) in patients with primary myelofibrosis or patients with polycythemia vera or essential thrombocythemia who secondarily evolved toward myelofibrosis or acute myeloid leukemia.
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Sabattini, Elena, Marco Pizzi, Claudio Agostinelli, et al. "Progression in Ph-Chromosome-Negative Myeloproliferative Neoplasms: An Overview on Pathologic Issues and Molecular Determinants." Cancers 13, no. 21 (2021): 5531. http://dx.doi.org/10.3390/cancers13215531.
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Progression in Ph-chromosome-negative myeloproliferative neoplasms (MPN) develops with variable incidence and time sequence in essential thrombocythemia, polycythemia vera, and primary myelofibrosis. These diseases show different clinic-pathologic features and outcomes despite sharing deregulated JAK/STAT signaling due to mutations in either the Janus kinase 2 or myeloproliferative leukemia or CALReticulin genes, which are the primary drivers of the diseases, as well as defined diagnostic criteria and biomarkers in most cases. Progression is defined by the development or worsening of marrow fibrosis or the progressive increase in the marrow blast percentage. Progression is often related to additional genetic aberrations, although some can already be detected during the chronic phase. Detailed scoring systems for clinical usage that are mostly applied in patients with primary myelofibrosis have been defined, and the most recent ones include cytogenetic and molecular parameters with prognostic significance. Additional different clinic-pathologic changes have been reported that may occur during the course of the disease and that are, at present, classified as WHO-defined types of progression, although they likely represent such an event. The present review is meant to provide an updated overview on progression in Ph-chromosome-negative MPN, with a major focus on the pathologic side.
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Alati, Caterina, Bruno Martino, Antonio Marino, Francesca Ronco, Manuela Priolo, and Francesco Nobile. "Familial Chronic Myeloproliferative Neoplasms." Blood 116, no. 21 (2010): 3078. http://dx.doi.org/10.1182/blood.v116.21.3078.3078.
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Abstract Abstract 3078 Chronic myeloproliferative neoplasms (CMNs) include Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). So far limited studies of familial clusters of CMNs have been reported.Familial chronic myeloproliferative neoplasms are defined when in the same pedigree at least two relatives have CMNs. Familial CMNs should be distinguished from inherited disorders with Mendelian transmission, high penetrance and polyclonal haematopoiesis named ‘hereditary erythrocytosis' and ‘hereditary thrombocytosis'. Recently a 5- to 7-fold higher risk of MPN among first-degree relatives of patients with MPNs was reported. These findings support the limited studies suggesting a familial clustering in MPNs. The analysis of mutations of JAK2 and MPL may improve our ability to identify these conditions. In a consecutive series of patients observed in our Institution from January 2000 to June 2010, we found that among 460 patients with sporadic CMNs and 94 Ph1 positive chronic myeloid leukemia (CML), the prevalence of familial cases was 4%.With 22 pedigrees, 44 patients (8%) were identified with two relatives affected. Familial CMNs were 11 PV,14 ET,7 PMF, 5 CML respectively, while sporadic cases were 96 PV,204 ET,115 PMF and with other 45 CMNS not furtherly classified. As far as the distribution of the different CMNs within the familial cluster, We observed that only in 4 of 22 families (18%) all the affected relatives were diagnosed with the same disease (homogeneous pattern: PV one family and ET three families), whereas 14 families exhibited a mixed distribution among PV, ET and PMF. 8 families exhibited CMNs associated with other hematological disease such as chrocic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodisplastic syndrome (MDS). Among this, 6 families presented a first or second degree of relationship of first and second generation. In 10 cases the relatives were brothers, affected by familial CMNs with a prevalence of PV and TE clinical phenotype at diagnosis.According to JAK2 (V617F) mutational status, analyzed in 30 out of 44 patients, 19 patients showed a positivity pattern, while 18 families showed a heterogeneous pattern; they included both JAK2 (V617F) -positive and JAK2 (V617F)-negative patients. Among the 19 patients with JAK2 (V617F) positivity, the distribution of positivity according to the diagnosis was 100% of PV, 45% of ET and 55%of PMF; homozygosity was present only in PV cases. In our series, only two members of the same family were affected by familial CMNs. Finally it should be noted that in our series of familial cases clinical presentation, therapeutic approach and type and severity of complications were comparable to that of sporadic cases. In conclusion, the present study indicates the relevant possibility of familial CMNs, thus suggesting the opportunity of a detailed family history as part of the initial work-up of patients with CMDs; in addition it also suggests the usefulness of an accurate biological study. Disclosures: No relevant conflicts of interest to declare.
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Gulbay, Gonca, Elif Yesilada, Mehmet Ali Erkurt, Harika Gozukara Bag, Irfan Kuku, and Emin Kaya. "Evaluation of the JAK2 V617F gene mutation in myeloproliferative neoplasms cases: a one-center study from Eastern Anatolia." Turkish Journal of Biochemistry 44, no. 4 (2019): 492–98. http://dx.doi.org/10.1515/tjb-2018-0054.
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AbstractObjectiveDetection ofJAK2V617F in myeloproliferative neoplasms (MPNs) is very important in both diagnosis and disease progression. In our study, we investigated the frequency ofJAK2V617F mutation in patients with myeloproliferative disorders.MethodsWe retrospectively reviewed the records of 720 patients (174 females and 546 males) who were tested for JAK2 V617F mutation from January 2007 to December 2017.ResultsIn our patients were determined 22.6%JAK2V617F mutation. 33.3% in women, 19.2% in men have been positive forJAK2V617F mutation. In our studyJAK2V617F present in 48.6% of essential thrombocythemia, 80.5% of polycythemia rubra vera (PV), 47.5% of primary myelofibrosis, 10% of MPNs, unclassifiable, 0.8% of others. We also investigated the difference in hematological parameters [white blood cell, hemoglobin (Hb), hematocrit (HCT), red blood cell distribution widths (RDW) and platelets count (PLT)] betweenJAK2V617F positive andJAK2V617F negative patients.ConclusionsInvestigation of the JAK2 V617F mutation is very important in cases of MPNs. In our study JAK2 V617F mutation was higher in PV, essential thrombocythemia, and primary myelofibrosis patients. However, there were significant differences in Hb, HCT, RDW and PLT levels in mutation-positive patients.
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Hoermann, Gregor, Georg Greiner, and Peter Valent. "Cytokine Regulation of Microenvironmental Cells in Myeloproliferative Neoplasms." Mediators of Inflammation 2015 (2015): 1–17. http://dx.doi.org/10.1155/2015/869242.
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The term myeloproliferative neoplasms (MPN) refers to a heterogeneous group of diseases including not only polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), but also chronic myeloid leukemia (CML), and systemic mastocytosis (SM). Despite the clinical and biological differences between these diseases, common pathophysiological mechanisms have been identified in MPN. First, aberrant tyrosine kinase signaling due to somatic mutations in certain driver genes is common to these MPN. Second, alterations of the bone marrow microenvironment are found in all MPN types and have been implicated in the pathogenesis of the diseases. Finally, elevated levels of proinflammatory and microenvironment-regulating cytokines are commonly found in all MPN-variants. In this paper, we review the effects of MPN-related oncogenes on cytokine expression and release and describe common as well as distinct pathogenetic mechanisms underlying microenvironmental changes in various MPN. Furthermore, targeting of the microenvironment in MPN is discussed. Such novel therapies may enhance the efficacy and may overcome resistance to established tyrosine kinase inhibitor treatment in these patients. Nevertheless, additional basic studies on the complex interplay of neoplastic and stromal cells are required in order to optimize targeting strategies and to translate these concepts into clinical application.
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Gardner, Jeffrey R., Omar Abdel-Wahab, Mark Frattini, et al. "High Mitochondrial Membrane Potential Identifies Patients with Myeloproliferative Neoplasms with a More Aggressive Natural History." Blood 116, no. 21 (2010): 1992. http://dx.doi.org/10.1182/blood.v116.21.1992.1992.
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Abstract Abstract 1992 The myeloproliferative neoplasms (MPN) can have a variable natural history. Polycythemia vera and essential thrombocythemia, in particular, are conditions that can extend over decades, but some patients have clinical progression to myelofibrosis or acute myeloid leukemia. As first articulated by Warburg, cancers are metabolically distinguished from normal tissues by the use of glycolysis under aerobic conditions. To metabolically characterize the blood cells of patients with myeloproliferative neoplasms, we measured the mitochondrial membrane potential using the cyanine dye, JC-1. In examining cells derived from the blood and/or marrow of 159 patients with primary myelofibrosis, polycythemia vera and essential thrombocythemia, we found that the mitochondrial membrane potential (FL2/FL1=electrochemical potential/mitochondrial mass) was elevated compared to the blood cells of normal individuals. Thirty five percent of patients with polycythemia vera and essential thrombocythemia had normal MMP. In contrast, 97% of patients with primary myelofibrosis, post-polycythemia myelofibrosis, post-essential thrombocythemia myelofibrosis and acute myeloid leukemia following an MPN had evidence of cell populations with higher mitochondrial membrane potential. Cells with distinctly higher mitochondrial membrane potential could be indentified in platelets and polymorphonuclear leukocytes; however the MMP of lymphocytes was normal, indicating that the alteration in metabolic state likely occurred in a multipotential myeloid stem cell. Cell populations were confirmed by co-staining with anti-CD19, -CD45, -GlycophorinA and -β3-integrin antibodies. Sequential analysis of patient samples found that the acquisition of higher mitochondrial membrane potential was stable and persistent over 2 years or more of follow up and that elevated membrane potential predisposed patients to disease progression. The balance of patients (65%) with ET had evidence of increased MMP suggesting the possibility of disease in an early state of evolution to a more aggressive condition. The increased MMP did not correlate with the presence of mutation in JAK2. These results indicate that clinically advanced MPN can be characterized by changes in mitochondrial physiology that might be identified non-invasively by flow cytometric staining with JC-1. In addition, the early nature of these changes may help to identify therapeutic targets. Disclosures: No relevant conflicts of interest to declare.
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Tsirakis, George, Peggy Kanellou, Maria Kaparou, et al. "Coexistence of Plasma Cell Dyscrasia with Prefibrotic Stage of Primary Myelofibrosis: A Case Report." ISRN Hematology 2011 (May 19, 2011): 1–3. http://dx.doi.org/10.5402/2011/404057.
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Introduction. Coexistence of myeloproliferative neoplasms with lymphoproliferative syndromes has been described in the past, whereas plasma cell dyscrasias seem to be the most common cases. Case Presentation. We present a case of a 59-year-old Caucasian female of Greek origin who presented with thrombocytosis. Clinical and laboratory investigation disclosed the presence of a smoldering myeloma with coexisting histological and molecular characteristics of primary myelofibrosis. The patient had the acquired point mutation V617F in the JAK2 gene but not the bcr-abl rearrangement and was treated for myelofibrosis with subsequent improvement of all haematological parameters without evidence of myelomatic evolution. Conclusion. We present the first case in the literature of a smoldering myeloma coexisting with primary myelofibrosis. The underlying pathogenetic mechanism could be either related to the presence of a pluripotent neoplastic stem cell capable to differentiate into both lymphoid and myeloid cells or be related to two separate nosologic entities.