Academic literature on the topic 'MiRna, Primary Myelofibrosis, Myeloproliferative Neoplasms'
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Journal articles on the topic "MiRna, Primary Myelofibrosis, Myeloproliferative Neoplasms"
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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 (December 2020): 91–109. http://dx.doi.org/10.1142/s2591722620400074.
Full textAbstract:
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, Elisa Bianchi, Simona Salati, Paola Guglielmelli, Andrea Bisognin, et al. "Regulatory Mrna/Microrna Networks in CD34+ Cells From Primary Myelofibrosis." Blood 120, no. 21 (November 16, 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, Elisa Bianchi, Simona Salati, Paola Guglielmelli, Andrea Bisognin, 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 (November 15, 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, Hideyoshi Noji, Hideo Kimura, Tatsuyuki Kai, Soji Morishita, Norio Komatsu, and Yasuchika Takeishi. "The Role Of Deregulated HMGA2 Expression With Promoter Methylation Of p16 In Myeloproliferative Neoplasms." Blood 122, no. 21 (November 15, 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, Roberta Zini, Samantha Ruberti, Elisa Bianchi, Simona Salati, 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 (December 2, 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 (December 6, 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, Simona Righi, Antonella Laginestra, Claudio Agostinelli, Elena Sabattini, et al. "Identification of Novel Cryptic Chromosomal Abnormalities in Primary Myelofibrosis by Single-Nucleotide Polymorphism Oligonucleotide Microarray." Blood 114, no. 22 (November 20, 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 (November 30, 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 (June 23, 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 (December 8, 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.
Dissertations / Theses on the topic "MiRna, Primary Myelofibrosis, Myeloproliferative Neoplasms"
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Pedrazzani, Fabiane Spagnol. "Impacto da análise molecular da mutação JAK2V617F no diagnóstico de neoplasias mieloproliferativas crônicas de acordo com os critérios da OMS 2016." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/157653.
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As neoplasias mieloproliferativas (NMPs) são um grupo de doenças derivadas de uma transformação clonal de célula tronco hematopoiéticas no qual a linhagem celular mielóide é predominantemente expandida no sangue periférico. As NMPs Philadelphia-negativas incluem policitemia vera (PV), trombocitemia essencial (TE) e mielofibrose primária (MFP) que compartilham muitas características hematológicas, clínicas e evolutivas. A mutação da JAK2 (JAK2V617F) está presente em cerca de 95% dos pacientes com PV, entre 50 a 70% com TE e 40 a 50% com MFP. No entanto, os testes moleculares para diagnóstico são muitas vezes um desafio devido ao alto custo e a disponibilidade de equipamentos especializados. Objetivo: Verificar o impacto do teste molecular da mutação JAK2V617F para o diagnóstico de NMPs nos pacientes atendidos no Hospital de Clínicas de Porto Alegre. Métodos: Foram avaliados 87 pacientes com suspeita de NMPs. As amostras de sangue periférico foram analisadas para a mutação JAK2V617F pelo método genético molecular de PCR alelo-específico e os resultados correlacionados com os dados clínico-laboratoriais. Para estabelecimento do diagnóstico, foram utilizados os critérios da Organização Mundial da Saúde (OMS) de 2016. Resultados: Dos 87 pacientes avaliados, 27,6% foram diagnosticados como PV, 39,1% como TE, 4,6% como MFP e 28,7% não contemplavam os critérios para o diagnóstico NMPs. A comparação da utilização do teste da mutação JAK2V617F mostrou que, apenas 41,7% dos pacientes com PV sem utilizar o teste, teriam sido diagnosticados comparados a 91,7% utilizando este teste como um dos critérios no diagnóstico final (p = 0,004). Na TE e na MFP, este critério não foi estatisticamente significativo. Conclusão: O teste molecular para a mutação de JAK2V617F no nosso hospital teve um impacto significativo no diagnóstico dos pacientes com PV, mostrando ser uma ferramenta importante para o diagnóstico final desta NMP.Myeloproliferative neoplasms (MPNs) are a group of disorders derived from a clonal transformation of stem cell on which myeloid cell lineage is predominantly expanded in the peripheral blood. Philadelphia-negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) which share many hematological, clinical, and evolutionary characteristics. The JAK2 mutation (JAK2V617F) is present in about 95% of patients with PV, between 50 to 70% with ET and 40 to 50% PMF. However, the molecular diagnostic tests are often a challenge due to the high cost and the availability of specialized equipment. Objective: To verify the impact of molecular testing of the JAK2V617F mutation for the diagnosis of MPNs in patients attended at Hospital de Clinics, Porto Alegre. Methods: A total of 97 patients were evaluated with suspected of MPNs. The peripheral blood samples were analyzed for the JAK2V617F mutation by the molecular genetic allelespecific PCR method and the results correlated with the clinical-laboratory data. To establish the diagnosis, the 2016 World Health Organization (WHO) criteria were used. Results: Of the 87 patients evaluated, 27.6% were diagnosed as PV, 39.1% as ET, 4.6% as PMF and 28.7% did not meet criteria for MPNs diagnosis. Comparison of the use of the JAK2V617F test showed that only 41.7% of patients with PV without the mutation test were diagnosed compared to 91.7% using this test as one of the criteria for the final diagnosis (p = 0.004). In the ET and the PMF, this criterion was not statistically significant. Conclusion: The molecular test for the JAK2V617F mutation in our hospital had a significant impact in the diagnosis of patients with PV, showing to be an important tool for the final diagnosis of this MPN.
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Orvain, Corentin. "Elaboration de nouveaux outils pour le diagnostic et le pronostic des patients atteints de syndrome myéloprolifératif. Circulating Cd34+ cell count differentiates primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms: a pragmatic study Sequential mutational evaluation of CALR-mutated myelopro-liferative neoplasms with thrombocytosis reveals an associa-tion between CALR allele burden evolution and diseaseprogression." Thesis, Angers, 2019. http://www.theses.fr/2019ANGE0043.
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Plusieurs scores pronostiques ont été élaboré chez les patients atteints de leucémie myéloïde chronique (LMC) sans qu’un lien n’ait été établi entre ces scores et la biologie de la LMC. Nous montrons que les patients de mauvais pronostic ont une expression accrue de GATA2, en corrélation avec les taux de basophiles et de plaquettes au diagnostic, paramètres utilisés dans le calcul des scores pronostiques, et à l’expression de gènes impliqués dans le fonctionnement des basophiles. Cette expression augmente lors de la transformation sur un versant myéloïde. Alors qu’un certain nombre de patients peuvent désormais tenter un arrêt de traitement avec un succès dans 50% des cas, il apparaît essentiel de revoir notre manière d’évaluer le pronostic. Ainsi, l’obtention d’une réponse moléculaire optimale dès 6 mois est associée avec une tentative ultérieure d’arrêt de traitement dans notre cohorte. Alors que le diagnostic de la LMC est relativement aisé, il est parfois difficile de différencier thrombocytémie essentielle (TE), pré-myélofibrose et myélofibrose. Nous réévaluons l’intérêt de la numération des cellules CD34+ circulantes: un nombre de cellules CD34+ circulantes < 10/μl permet d’exclure le diagnostic de myélofibrose avec une très bonne sensibilité (97%) et spécificité (90%). Dans une cohorte de patients atteints de TE avec mutation CALR, nous montrons que l’augmentation de sa charge allélique, et non la présence de mutations additionnelles, est associée à un risque accru de progression. L’ensemble de ces paramètres sera étudié dans une étude prospective multicentrique visant à établir un score diagnostique non invasif permettant de différencier TE, pré-myélofibrose et myélofibroseVarious scoring systems have been successively elaborated to predict outcome of patients with chronic myeloid leukemia (CML). However, no link has been identified between those scores and CML biology. We show that high-risk patients have high GATA2 levels, in correlation with higher baseline basophil and platelet counts, two parameters used to calculate prognostic scores, and expression of genes involved in basophils. GATA2 expression increases in accelerated and myeloidblast-phase. Since some patients can now stop treatment, with a near 50% success rate, it is necessary to reevaluate the way we assess prognosis. A 6-month optimal molecular response was associated with an increased discontinuation attempt rate in our cohort. While the diagnosis of CML is fairly easy, it is often difficult to distinguish essential thrombocythemia (ET), pre-myelofibrosis and myelofibrosis. The numeration of CD34+ circulating cells is of interest in this setting : we show that a number < 10/μ excludes the diagnosis of myelofibrosis with a very good sensitivity (97%) and good specificity (90%). In a cohort of patients with ET and CALR mutation, We show that an increase in allele burden, and not additional mutations at diagnosis or during follow-up,is associated with an increased risk of progression. All of these parameters will be evaluated in a prospective multicentric study in order to elaborate a non-invasive diagnostic score to distinguish TE, pre-myélofibrosis, and myelofibrosis
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MANNARELLI, CARMELA. "“MiRNA expression in Primary Myelofibrosis: characterization and pathophysiology implications”." Doctoral thesis, 2016. http://hdl.handle.net/2158/1039412.
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Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by megakaryocyte (MK) hyperplasia, bone marrow fibrosis, and abnormal stem cell trafficking. PMF may be associated with somatic mutations, about 90% of patients harbor one of three “driver” mutations, with mutational frequencies of approximately 60%, 22% and 6% for JAK2, CALR and MPL, respectively. Other “non-driver” mutations have also been described in PMF involving different cellular targets such as epigenetic regulatory pathways genes (ASXL1, DNMT3A, EZH2, IDH1 and IDH2, TET2), splicing factor genes (SRSF2, SF3B1) and progression to leukemia (CBL, LNK, RUNX1, TP53). However, several aspects of its pathogenesis remain elusive. Increasing evidences indicate that the deregulation of microRNAs (miRNAs) might plays an important role in hematologic malignancies, including MPN. In this work, in collaboration with a group at the Hemopoietic Stem Cells Laboratory of the University of Modena and Reggio Emilia and a bioinformatics group of University of Padua, it was performed a genome wide analysis of coding RNA (GEP) and microRNA (miEP) expression in CD34+ cells purified from patients with PMF and from health subjects initially using Affymetrix technology. By means of miRNA-gene expression integrative analysis, it was found different regulatory networks involved in the dysregulation of transcriptional control and chromatin remodeling. In particular, it was identified a network gathering several miRNAs with oncogenic potential (e.g. miR-155-5p) and targeted genes whose abnormal function has been previously associated with myeloid neoplasms, including JARID2, NR4A3, CDC42, and HMGB3. Because the validation of miRNA-target interactions unveiled JARID2/miR-155-5p as the strongest relationship in the network, it was studied the function of this axis in normal and PMF CD34+ cells. This study showed that JARID2 downregulation mediated by miR-155-5p overexpression leads to increased in vitro formation of CD41+ MK precursors. These findings suggest that overexpression of miR-155-5p and the resulting downregulation of JARID2 may contribute to MK hyperplasia in PMF.
At the same time, to attain deeper and more extensive knowledge of short RNAs (sRNAs) expression pattern in CD34+ cells and of their possible role in mediating post-transcriptional regulation in PMF, CD34+ cells from healthy subjects and PMF patients were sequenced with Illumina HiSeq2000 technology. It was detected the expression of 784 known miRNAs, with a prevalence of miRNA up-regulation in PMF samples, and discovered 34 new miRNAs and 99 new miRNA-offset RNAs (moRNAs) in CD34+ cells. Thirty-seven small RNAs were differentially expressed in PMF patients compared with healthy subjects, according to microRNA sequencing data. Five miRNAs (miR-10b-5p, miR-19b-3p, miR-29a-3p, miR-379-5p, and miR-543) were deregulated also in PMF granulocytes. Moreover, 3’-moR-128-2 resulted consistently downregulated in PMF according to RNA-seq and qRT-PCR data both in CD34+ cells and granulocytes. Target predictions of these validated small RNAs de-regulated in PMF and functional enrichment analyses highlighted many interesting pathways involved in tumor development and progression, such as signaling by FGFR and DAP12 and Oncogene Induced Senescence. As a whole, data obtained in this study deepened the knowledge of miRNAs and moRNAs altered expression in PMF CD34+ cells and allowed to identify and validate a specific small RNA profile that distinguishes PMF granulocytes from those of normal subjects. It was thus provided new information regarding the possible role of miRNAs and, specifically, of new moRNAs in this disease.
The expression of 175 miRnas in plasma samples was also analyzed in the patients with PMF and the healthy donors and it was identified the presence of 6 differentially expressed miRNAs deregulated in significant statistically way (P value <0.05): miR-let7b*, miR-10b-5p, miR-424 and miR-99a were resulted up-regulated instead miR-144* and miR-375 were down-regulated in PMF patients. These data show a distinct plasma miRNA expression patterns in patients with PMF compared with health subjects which could have a potential utility as prognostic biomarkers. Finally, in order to clarify the contribution of microRNAs also in to the pathogenesis of JAK2V617F-positive MPNs, it was analysed the miRNAs expression pattern in erythroid (TER119+) and mieloid (GR1+) cells purified from BM of JAK2V617F knock-in (KI) mouse model using TaqMan® Real time PCR. In this part of the study, it was identified a list of differentially expressed miRNAs also in JAK2V617F KI mouse whose deregulation might contribute to the development and phenotype of MPNs.
The results of this work provided novel data regarding the expression profile of small RNA expressed in CD34+, granulocytes and plasma of PMF patients; in addition, for the first time a new moRNAs was described as possible contributors to disease pathogenesis. Finally, it was identified a list of differentially expressed miRNAs in JAK2V617F KI mouse whose deregulation might contribute to the development/phenotype of MPNs. This information may represent the basis for further studies aimed at a deeper knowledge of the prognostic and therapeutical role of miRNAs and also moRNAs in PMF.
Books on the topic "MiRna, Primary Myelofibrosis, Myeloproliferative Neoplasms"
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Provan, Drew, Trevor Baglin, Inderjeet Dokal, and Johannes de Vos. Myeloproliferative neoplasms. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199683307.003.0007.
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Myeloproliferative neoplasms (MPNs) - Pathogenesis of the MPNs - Polycythaemia vera (PV) - Natural history of PV - Management of PV - Secondary erythrocytosis - Relative erythrocytosis - Idiopathic erythrocytosis - Essential thrombocythaemia - Reactive thrombocytosis - Primary myelofibrosis - Chronic neutrophilic leukaemia - Eosinophilic syndromes and neoplasms - Mastocytosis (mast cell disease) - Systemic mastocytosis - MPN—unclassifiable
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Provan, Drew, Trevor Baglin, Inderjeet Dokal, Johannes de Vos, and Mammit Kaur. Myeloproliferative neoplasms. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199683307.003.0007_update_001.
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Myeloproliferative neoplasms (MPNs) - Pathogenesis of the MPNs - Polycythaemia vera (PV) - Natural history of PV - Management of PV - Secondary erythrocytosis - Relative erythrocytosis - Idiopathic erythrocytosis - Essential thrombocythaemia - Reactive thrombocytosis - Primary myelofibrosis - Chronic neutrophilic leukaemia - Eosinophilic syndromes and neoplasms - Mastocytosis (mast cell disease) - Systemic mastocytosis - MPN—unclassifiable
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Mughal, Tariq I., and Tiziano Barbui, eds. Oxford Specialist Handbook: Myeloproliferative Neoplasms. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.001.0001.
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Our understanding of myeloproliferative neoplasms (MPN) disorders, a group of clonal haematological malignancies characterized by excessive accumulation of one or more myeloid cell lineages, has grown considerably over the past four decades. Even more importantly is the speed at which many of these findings were translated to accord survival benefits to our patients with MPN, in particular chronic myeloid leukaemia (CML), polycythaemia vera (PV), essential thrombocythaemia (ET), and primary myelofibrosis (PMF). This text offers a detailed evidence-based guide to MPN in an easily accessible format, structure to facilitate learning specialist information presenting core information in ‘bite size’ chunks. Each chapter summarizes the state-of-the art preclinical and clinical knowledge, and its impact on the clinical management of patients with MPN.
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Collins, Graham, and Chris Bunch. Myeloproliferative disorders. Edited by Patrick Davey and David Sprigings. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199568741.003.0291.
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Myeloproliferative disorders (also called myeloproliferative neoplasms) can be defined as clonal haematopoietic disorders resulting in excess production of one or more blood cell lineage. The four main conditions are primary polycythaemia, which is characterized by excess red-cell production; essential thrombocythaemia, which is characterized by excess platelet production; chronic myeloid leukaemia, which is characterized by excess granulocyte production; and myelofibrosis, which is characterized by excess megakaryocyte proliferation, which results in a reactive fibroblast proliferation causing marrow fibrosis and failure. This chapter addresses the causes, diagnosis, and management of these myeloproliferative disorders.
Book chapters on the topic "MiRna, Primary Myelofibrosis, Myeloproliferative Neoplasms"
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Barosi, Giovanni. "Conventional and Investigational Therapy for Primary Myelofibrosis." In Myeloproliferative Neoplasms, 117–38. Totowa, NJ: Humana Press, 2010. http://dx.doi.org/10.1007/978-1-60761-266-7_6.
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Tefferi, Ayalew. "Myeloproliferative Neoplasms: Essential Thrombocythemia, Polycythemia Vera, and Primary Myelofibrosis." In Practical Hemostasis and Thrombosis, 147–56. Oxford, UK: Wiley-Blackwell, 2010. http://dx.doi.org/10.1002/9781444306286.ch14.
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Tibes, Raoul, Gurcharan Singh Khera, and Ruben A. Mesa. "Myeloproliferative Neoplasms: Chronic Myelogenous Leukemia, Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis." In Textbook of Uncommon Cancer, 647–58. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2012. http://dx.doi.org/10.1002/9781118464557.ch47.
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Harrison, Claire, Yan Beauverd, and Donal McLorran. "Myelofibrosis." In Oxford Specialist Handbook: Myeloproliferative Neoplasms, 126–50. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.003.0009.
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The World Health Organization (WHO) classification defines myelofibrosis (MF) to comprise of the three principal subtypes, primary myelofibrosis, post-polycythaemia vera myelofibrosis, and post-essential thrombocythaemia. Each subtype appears to exhibit a similar pathogenesis, clinical presentation, evolution, and treatment. The critical driver mutations involved in the pathogenesis are be JAK2, MPL, or CALR; mutations in the splicing machinery genes, the epigenome, transcription factors, and dysregulation in the haematopoietic stem cell niche also play pathogenetic roles. Myelofibrosis is a progressive disease, often evolves from a precursor disease state without any clinical symptoms and few laboratory anomalies, to more advanced stages with substantial symptom-burden. Janus kinase (JAK) inhibitors, such as ruxolitinib, afford significant symptomatic benefit, but no major impact on the JAK2 allelic burden, and many patients are offered a risk-adapted approach.
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Jasielec, Jagoda, and Olatoyosi Odenike. "Primary, Post-PV, and Post-ET Myelofibrosis: Clinical Features, Prognosis, and Conventional Therapy." In Contemporary Management of Myeloproliferative Neoplasms, 102. Jaypee Brothers Medical Publishers (P) Ltd., 2015. http://dx.doi.org/10.5005/jp/books/12391_6.
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Abdelwahab, Omar, Raajit Rampal, Catriona Jamieson, and Tariq I. Mughal. "Transformation of myeloproliferative neoplasms to acute leukaemia." In Oxford Specialist Handbook: Myeloproliferative Neoplasms, 222–33. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.003.0014.
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Clinically chronic myeloproliferative neoplasms are biphasic or triphasic diseases that are usually diagnosed in the initial ‘chronic’, ‘indolent’, or ‘stable’ phase and then spontaneously evolve after some years into an advanced phase. In patients with chronic myeloid leukaemia, the advanced phase can sometimes be subdivided into an earlier accelerated phase and a later blast phase resembling acute leukaemia. Patients with essential thrombocythaemia and polycythaemia vera transform initially to myelofibrosis and then to acute myeloid leukaemia (AML). Rarely they transform directly from the initial indolent phase to AML; patients with primary myelofibrosis also transform directly to AML. Although much is known about the molecular biology and genomic landscape of the initial phases, the molecular basis of disease progression and transformation remains obscure. The clinical management of transformed disease is generally difficult, and most patients tend to have a poor prognosis. This chapter reviews what is known of the mechanisms underlying the transformation of these myeloproliferative neoplasms from a chronic phase to frank leukaemia and also discusses the current and future treatment strategies.
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Egan, Daniel, and Jerald P. Radich. "Monitoring efforts in myeloproliferative neoplasms." In Oxford Specialist Handbook: Myeloproliferative Neoplasms, 234–48. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.003.0015.
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Targeted therapy with tyrosine kinase inhibitors (TKI) has transformed the therapy of chronic myeloid leukaemia (CML), and is increasingly playing a role in the management of the myeloproliferative neoplasms (MPN), as a whole. In CML, the Philadelphia chromosome drives disease pathogenesis, and is the basis of both therapy (aimed at the BCR-ABL protein) and monitoring (the BCR-ABL chimeric mRNA). The efficacy of tyrosine kinase inhibitor therapy in CML is now accessed by reaching treatment milestones based on the BCR-ABL mRNA levels. In MPN, the landscape of genetic mutations associated with essential thrombocytosis (ET), polycythaemia vera (PV), and primary myelofibrosis (PMF) is ongoing. However, the recent discoveries of the JAK2 V617F and calreticulin mutations (for example) have a similar potential for disease targeting and monitoring as in CML.
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Kvasnicka, Hans Michael, and Jürgen Thiele. "Haematopathology of classic myeloproliferative neoplasms." In Oxford Specialist Handbook: Myeloproliferative Neoplasms, 45–62. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.003.0004.
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The classification of the World Health Organization (WHO) continues to advocate the diagnostic importance of bone marrow (BM) morphology in the diagnostic workup of myeloproliferative neoplasms (MPN). In this regard, distinctive histological BM patterns characterize specific subtypes of MPN and are the key to a meaningful clinical and molecular-defined risk stratification of patients. In this regard, the morphological denominator includes a characteristic megakaryocytic proliferation along with variable changes in the granulopoiesis and erythropoiesis. Importantly, diagnosis of MPN requires absence of relevant dysgranulopoiesis or dyserythropoiesis. In terms of clinical practice, the concept of precursor stages provides the possibility of an early intervention by appropriate therapeutic regimens that might prevent fatal complications like thrombosis and haemorrhage, especially in early stages of polycythaemia vera or in primary myelofibrosis. However, the WHO classification is not aimed to capture all biological true cases of MPN or guarantee a complete diagnostic specificity and thus might be in need of continuous improvement following clinical experience.
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Besses, Carlos, Beatriz Bellosillo, Alberto Alvarez-Larrán, and Tariq I. Mughal. "Essential thrombocythaemia." In Oxford Specialist Handbook: Myeloproliferative Neoplasms, 151–67. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198744214.003.0010.
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Essential thrombocythaemia is a classic myeloproliferative neoplasm characterized by thrombocytosis, increased risk of thrombotic and/or haemorrhagic complications, and a trend to transformation to myelofibrosis and acute leukaemia. Mutations in JAK2, CALR, and MPL genes besides bone marrow histology are crucial elements of diagnosis. Treatment is aimed to prevent the appearance of thrombotic complications that are the main cause of morbidity and mortality. Accordingly, thrombosis risk stratification is of the utmost importance to select the appropriate treatment. Antiplatelet therapy as primary antithrombotic prophylaxis in low-risk patients should be tailored according to the existence of extreme thrombocytosis and presence of JAK2V617F mutation and/or cardiovascular risk factors. Cytoreductive treatment options are discussed with reference to results of randomized clinical trials. Practical approach to unusual and risk situations as surgery, pregnancy, and paediatric essential thrombocythaemia are also reviewed.
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Hoover, Kevin B. "Lymphoproliferative and Myeloproliferative Disorders." In Musculoskeletal Imaging Volume 2, edited by Kevin B. Hoover, 44–49. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780190938178.003.0078.
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Chapter 78 discusses lymphoproliferative and myeloproliferative disorders, which are a disparate group of premalignant and malignant neoplasms originating in or metastasizing to the bone marrow. Included in this group of disorders is primary myelofibrosis, systemic mastocytosis, leukemia, and lymphoma. Because these tend to involve the marrow more often than the cortex, they are best detected by MRI and nuclear imaging techniques, including FDG-PET and CT. Distinguishing the disorders by imaging is often difficult because of the overlap in imaging findings. Imaging is beneficial to guide biopsy, which is crucial in diagnosis, and to assess treatment response.