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)

Myelofibrosis (MF; primary or post-essential thrombocythemia/polycythemia vera) is incurable clonal myeloproliferative disorder, with no effective treatment. Epigenetic changes play an important role in cancer pathogenesis through transcriptional silencing of critical tumor suppressor genes. We conducted a phase-II study to evaluate the activity of DNA methyltransferase inhibitor, 5-azacitidine, in patients with MF. Thirty-four patients (76% previously treated) received 5-azacitidine at 75 mg/m(2) subcutaneously daily for 7 days, every 4 weeks. Twelve (35%) patients had abnormal cytogenetics and 19 (70%) of 27 evaluable patients had JAK2(V617F) mutation. Responses occurred in 8 (24%) patients after a median of 5 months (range, 3-10). Partial response occurred in 1 (3%) patient (duration 22+ months) and clinical improvement in 7 (21%) patients (median duration 4 months; range, 2-8.5). Myelosuppression was the major adverse effect, with grade 3-4 neutropenia in 10 (29%) patients. Global DNA methylation assessed by the long interspersed nucleotide element (LINE) bisulfite/pyrosequencing assay decreased from 53% pretherapy to 44% on day 14 (P=0.0014) and returned to 50% at the end of the first 28-day cycle (P=0.016). 5-azacitidine is relatively well tolerated and results in induction of global hypomethylation in patients with MF, but results in limited clinical activity.
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PMID:A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis. 1850 50

The myeloproliferative neoplasms (MPNs) are a group of clonal hematological malignancies characterized by a hypercellular bone marrow and a tendency to develop thrombotic complications and to evolve to myelofibrosis and acute leukemia. Unlike chronic myelogenous leukemia, where a single disease-initiating genetic event has been identified, a more complicated series of genetic mutations appear to be responsible for the BCR-ABL1-negative MPNs which include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Recent studies have revealed a number of epigenetic alterations that also likely contribute to disease pathogenesis and determine clinical outcome. Increasing evidence indicates that alterations in DNA methylation, histone modification, and microRNA expression patterns can collectively influence gene expression and potentially contribute to MPN pathogenesis. Examples include mutations in genes encoding proteins that modify chromatin structure (EZH2, ASXL1, IDH1/2, JAK2V617F, and IKZF1) as well as epigenetic modification of genes critical for cell proliferation and survival (suppressors of cytokine signaling, polycythemia rubra vera-1, CXC chemokine receptor 4, and histone deacetylase (HDAC)). These epigenetic lesions serve as novel targets for experimental therapeutic interventions. Clinical trials are currently underway evaluating HDAC inhibitors and DNA methyltransferase inhibitors for the treatment of patients with MPNs.
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PMID:Epigenetic abnormalities in myeloproliferative neoplasms: a target for novel therapeutic strategies. 2270 37

Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by increased production of mature blood cells. Philadelphia chromosome-negative MPNs (Ph-MPNs) consist of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). A number of stem cell derived mutations have been identified in the past 10 years. These findings showed that JAK2V617F, as a diagnostic marker involving JAK2 exon 14 with a high frequency, is the best molecular characterization of Ph-MPNs. Somatic mutations in an endoplasmic reticulum chaperone, named calreticulin (CALR), is the second most common mutation in patients with ET and PMF after JAK2 V617F mutation. Discovery of CALR mutations led to the increased molecular diagnostic of ET and PMF up to 90%. It has been shown that JAK2V617F is not the unique event in disease pathogenesis. Some other genes' location such as TET oncogene family member 2 (TET2), additional sex combs-like 1 (ASXL1), casitas B-lineage lymphoma proto-oncogene (CBL), isocitrate dehydrogenase 1/2 (IDH1/IDH2), IKAROS family zinc finger 1 (IKZF1), DNA methyltransferase 3A (DNMT3A), suppressor of cytokine signaling (SOCS), enhancer of zeste homolog 2 (EZH2), tumor protein p53 (TP53), runt-related transcription factor 1 (RUNX1) and high mobility group AT-hook 2 (HMGA2) have also identified to be involved in MPNs phenotypes. Here, current molecular biology and genetic mechanisms involved in MNPs with a focus on the aforementioned factors is presented.
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PMID:Myeloproliferative neoplasms: Current molecular biology and genetics. 2669 89