Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032463 (polycythemia vera)
 3,374 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. To help identify novel mutations in myeloproliferative neoplasms (MPNs), we performed a genome-wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n = 30), JAK2 mutation-negative myelofibrosis (MF; n = 18), or JAK2 mutation-negative polycythemia vera (PV; n = 10). Stretches of homozygous, copy neutral SNP calls greater than 20Mb were seen in 10 (33%) aCML and 1 (6%) MF, but were absent in PV. In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 CBL variants in 26 patients with aCML, myelofibrosis or chronic myelomonocytic leukemia. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs.
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PMID:Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. 1938 8

During these past 5 years several studies have provided major genetic insights into the pathogenesis of the so-called classical myeloproliferative neoplasms (MPNs): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The discovery of the JAK2V617F mutation first, then of the JAK2 exon 12 and MPLW515 mutations, have modified the understanding of these diseases, their diagnosis, and management. Now it is established that almost 100% of PV patients present a JAK2 mutation. Nearly 60% of ET patients and 50% of patients with PMF have the JAK2V617F mutation. The MPLW515 mutations are also present in a small proportion of ET and PMF patients. These mutations are oncogenic events that cause these disorders; however, they do not explain the heterogeneity of the entities in which they occur. Genetic defects have not been yet identified in around 40% of ET and PMF. There are likely additional somatic genetic factors important for the MPN phenotype like the recently described TET2, ASXL1, and CBL mutations. Moreover, polymorphisms in the JAK2 gene have been recently described as associated with MPN. Additional studies of large cohorts are required to dissect the genetic events in MPNs and the mechanisms of these oncogenic cooperations.
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PMID:Molecular aspects of myeloproliferative neoplasms. 2018 5

Myeloproliferative neoplasms (MPNs) originate from genetically transformed hematopoietic stem cells that retain the capacity for multilineage differentiation and effective myelopoiesis. Beginning in early 2005, a number of novel mutations involving Janus kinase 2 (JAK2), Myeloproliferative Leukemia Virus (MPL), TET oncogene family member 2 (TET2), Additional Sex Combs-Like 1 (ASXL1), Casitas B-lineage lymphoma proto-oncogene (CBL), Isocitrate dehydrogenase (IDH) and IKAROS family zinc finger 1 (IKZF1) have been described in BCR-ABL1-negative MPNs. However, none of these mutations were MPN specific, displayed mutual exclusivity or could be traced back to a common ancestral clone. JAK2 and MPL mutations appear to exert a phenotype-modifying effect and are distinctly associated with polycythemia vera, essential thrombocythemia and primary myelofibrosis; the corresponding mutational frequencies are approximately 99, 55 and 65% for JAK2 and 0, 3 and 10% for MPL mutations. The incidence of TET2, ASXL1, CBL, IDH or IKZF1 mutations in these disorders ranges from 0 to 17%; these latter mutations are more common in chronic (TET2, ASXL1, CBL) or juvenile (CBL) myelomonocytic leukemias, mastocytosis (TET2), myelodysplastic syndromes (TET2, ASXL1) and secondary acute myeloid leukemia, including blast-phase MPN (IDH, ASXL1, IKZF1). The functional consequences of MPN-associated mutations include unregulated JAK-STAT (Janus kinase/signal transducer and activator of transcription) signaling, epigenetic modulation of transcription and abnormal accumulation of oncoproteins. However, it is not clear as to whether and how these abnormalities contribute to disease initiation, clonal evolution or blastic transformation.
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PMID:Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. 2042 94

Philadelphia negative myeloproliferative neoplasms include essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Altered signaling is a hallmark of myeloproliferative neoplasms, as demonstrated by the presence of activating JAK2 (V617F) mutation in about 70% of patients (95% of polycythemia vera, 50%-60% of essential thrombocythemia, and 50%-60% of primary myelofibrosis). How a unique point mutation can cause three different phenotypes remains to be clarified. The oncogenic potential of this mutation has been documented by mouse models, and different clinical studies have demonstrated an effect of mutant allele burden on phenotype. Mutant allele burden, in fact, directly correlates with hemoglobin value, leukocyte count, and, inversely, with platelet count. The molecular basis of JAK2 (V617F)-negative myeloproliferative neoplasms remains largely unexplained. Additional mutations in MPL, TET2, and CBL genes have been found in a small proportion of these patients. Implications of these mutations in the understanding of the pathogenesis of myeloproliferative neoplasms and in the clinical phenotype are discussed in this review.
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PMID:Mutational status of myeloproliferative neoplasms. 2052 38

To update oncologists on pathogenesis, contemporary diagnosis, risk stratification, and treatment strategies in BCR-ABL1-negative myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Recent literature was reviewed and interpreted in the context of the authors' own experience and expertise. Pathogenetic mechanisms in PV, ET, and PMF include stem cell-derived clonal myeloproliferation and secondary stromal changes in the bone marrow and spleen. Most patients carry an activating JAK2 or MPL mutation and a smaller subset also harbors LNK, CBL, TET2, ASXL1, IDH, IKZF1, or EZH2 mutations; the precise pathogenetic contribution of these mutations is under investigation. JAK2 mutation analysis is now a formal component of diagnostic criteria for PV, ET, and PMF, but its prognostic utility is limited. Life expectancy in the majority of patients with PV or ET is near-normal and disease complications are effectively (and safely) managed by treatment with low-dose aspirin, phlebotomy, or hydroxyurea. In PMF, survival and quality of life are significantly worse and current therapy is inadequate. In ET and PV, controlled studies are needed to show added value and justify the risk of unknown long-term health effects associated with nonconventional therapeutic approaches (eg, interferon-alfa). The unmet need for treatment in PMF dictates a different approach for assessing the therapeutic value of new drugs (eg, JAK inhibitors, pomalidomide) or allogeneic stem-cell transplantation.
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PMID:Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. 2157 37

Most BCR-ABL1-negative myeloproliferative neoplasms (MPN) carry an activating JAK2 mutation. Approximately 96% of patients with polycythemia vera (PV) harbors the V617F mutation in JAK2 exon 14, whereas the minority of JAK2 (V617F)-negative subjects shows several mutations in exon 12. Other mutation events as MPL, TET2, LNK, EZH2 have been described in chronic phase, while NF1, IDH1, IDH2, ASX1, CBL and Ikaros in blast phase of MPN. The specific pathogenic implication of these mutations is under investigation, but they may have a role in refinement of diagnostic criteria and in development of new prognostic models. Several trials with targeted therapy (JAK inhibitors) are ongoing mostly involving patients with PMF, post-PV MF and post-essential thrombocythemia (ET) MF. Treatment with ruxolitinib and TG101348 has shown clinically significant benefits, particularly in improvement of splenomegaly and constitutional symptoms in MF patients. On the other hand, JAK inhibitors have not thus far shown disease-modifying activity therefore any other deduction on these new drugs seems premature.
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PMID:Myeloproliferative neoplasms: from JAK2 mutations discovery to JAK2 inhibitor therapies. 2164 83

Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by excessive production of mature blood cells. In the majority of classic MPN--polycythemia vera, essential thrombocythemia, and primitive myelofibrosis--driver oncogenic mutations affecting Janus kinase 2 (JAK2) or MPL lead to constitutive activation of cytokine-regulated intracellular signaling pathways. LNK, c-CBL, or SOCSs (all negative regulators of signaling pathways), although infrequently targeted, may either drive the disease or synergize with JAK2 and MPL mutations. IZF1 deletions or TP53 mutations are mainly found at transformation phases and are present at greater frequency than in de novo acute myeloid leukemias. Loss-of-function mutations in 3 genes involved in epigenetic regulation, TET2, ASXL1, and EZH2, may be early events preceding JAK2V617F but may also occur late during disease progression. They are more frequently observed in PMF than PV and ET and are also present in other types of malignant myeloid diseases. A likely hypothesis is that they facilitate clonal selection, allowing the dominance of the JAK2V617F subclone during the chronic phase and, together with cooperating mutations, promote blast crisis. Their precise roles in hematopoiesis and in the pathogenesis of MPN, as well as their prognostic impact and potential as a therapeutic target, are currently under investigation.
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PMID:New mutations and pathogenesis of myeloproliferative neoplasms. 2165 28

Mutations in the TET2 and ASXL1 genes have been described in approximately 14% and 8% of patients, respectively, with classic myeloproliferative neoplasms (MPN), but their role as possible new diagnostic molecular markers is still inconclusive. In addition, other genes such as IDH1, IDH2, and c-CBL have also been reported in several myeloid neoplasms. We have studied the mutational status of TET2 (complete coding region), ASXL1 (exon12), IDH1 (R132), IDH2 (R140 and R172), and c-CBL (exons 8 and 9) in 62 MPN patients (52 essential thrombocythemia (ET), five polycythemia vera (PV), and five primary myelofibrosis (PMF)) negative for both JAK2 (V617F and exon 12) and MPL (exon 10) mutations. Pathogenic alterations in the TET2 gene were detected in three out 52 ET cases (4.8%). ASXL1 gene pathogenic mutations were also detected in three cases (two ET and one PMF). One ET patient harbored, simultaneously, one TET2 and one ASXL1 mutations. Mutations in the TET2 and ASXL1 genes showed no association with the JAK2 46/1 haplotype. Analysis of a JAK2V617F-positive cohort of 50 ET patients showed no mutations in either the TET2 or ASXL1 genes. Regarding IDH1, IDH2, and c-CBL genes, no mutations were found in any patient. In conclusion, TET2 and ASXL1 pathogenic mutations are found in 8% of MPN lacking JAK2 and MPL mutations, whereas IDH1, IDH2, and c-CBL mutations are not detected in this subset of patients.
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PMID:TET2, ASXL1, IDH1, IDH2, and c-CBL genes in JAK2- and MPL-negative myeloproliferative neoplasms. 2190 53

Since the discovery of the JAK2V617F tyrosine kinase-activating mutation several genes have been found mutated in nonchronic myeloid leukemia (CML) myeloproliferative neoplasms (MPNs), which mainly comprise three subtypes of "classic" MPNs; polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). We searched for mutations in ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 genes in 149 non-CML MPNs, including 127 "classic" MPNs cases. JAK2 was mutated in 100% PV, 66% ET and 68% MF. We found a high incidence of ASXL1 mutation in MF patients (20%) and a low incidence in PV (7%) and ET (4%) patients. Mutations in the other genes were rare (CBL, DNMT3A, IDH2, MPL, SF3B1, SUZ12, NF1) or absent (IDH1).
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PMID:Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms. 2248 43

We investigated 15,542 patients with suspected BCR-ABL1- negative myeloproliferative or myelodysplastic/myeloproliferative neoplasm (including 359 chronic myelomonocytic leukemia) by a molecular marker set. JAK2V617F was detected in the suspected categories as follows: polycythemia vera 88.3%, primary myelofibrosis 53.8%, essential thrombocythemia 50.2%, and not further classifiable myeloproliferative neoplasms 38.0%. JAK2 exon 12 mutations were detected in 40.0% JAK2V617F-negative suspected polycythemia vera, MPLW515 mutations in 13.2%JAK2V617F-negative primary myelofibrosis and 7.1% JAK2V617F-negative essential thrombocythemia. TET2 mutations were distributed across all entities but were most frequent in suspected chronic myelomonocytic leukemia (77.8%). CBL mutations were identified in suspected chronic myelomonocytic leukemia (13.9%), primary myelofibrosis (8.0%), and not further classifiable myeloproliferative neoplasm (7.0%). This leads to a stepwise workflow for suspected myeloproliferative neoplasms starting with JAK2V617F and investigating JAK2V617F-negative patients for JAK2 exon 12 or MPL mutations, respectively. In cases in which a myeloproliferative neoplasm cannot be established, analysis for TET2, CBL and EZH2 mutations may be indicated.
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PMID:Molecular analyses of 15,542 patients with suspected BCR-ABL1-negative myeloproliferative disorders allow to develop a stepwise diagnostic workflow. 2251 94


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