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

Imatinib mesylate, a small molecule tyrosine kinase inhibitor, has had a major impact on the treatment of Philadelphia chromosome positive chronic myelogenous leukemia. This review will explore its potential in the treatment of other myeloid neoplasms, based on its ability to inhibit Kit and PDGFR kinases in addition to Bcr-Abl. Imatinib's potential role in the treatment of Philadelphia chromosome negative chronic myelogenous leukemia, systemic mastocytosis with associated hematologic neoplasms, chronic myelomonocytic leukemia, specific subtypes of acute myelogenous leukemia, myelofibrosis/myeloid metaplasia, and polycythemia vera is discussed.
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PMID:Imatinib mesylate (STI571) for myeloid malignancies other than CML. 1503 42

Imatinib mesylate has recently been reported to have clinical activity in the treatment of polycythemia vera (PV), suggesting the involvement of one of the kinases targeted by this inhibitor, including c-Kit and PDGFR. Activating c-Kit mutations have been identified in patients with mastocytosis and other myeloid disorders such as acute myeloid leukemia. Thus, we wanted to analyze the presence of mutations of c-Kit in polycythemia vera patients. We found that 7 out of 20 patients carried missense mutations in the c-Kit gene whereas no sequence variation was detected in 15 healthy controls.
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PMID:Identification of c-Kit gene mutations in patients with polycythemia vera. 1646 Aug 1

Therapeutically validated oncoproteins in myeloproliferative neoplasms (MPN) include BCR-ABL1 and rearranged PDGFR proteins. The latter are products of intra- (e.g. FIP1L1-PDGFRA) or inter-chromosomal (e.g. ETV6-PDGFRB) gene fusions. BCR-ABL1 is associated with chronic myelogenous leukaemia (CML) and mutant PDGFR with an MPN phenotype characterized by eosinophilia and in addition, in case of FIP1L1-PDGFRA, bone marrow mastocytosis. These genotype-phenotype associations have been effectively exploited in the development of highly accurate diagnostic assays and molecular targeted therapy. It is hoped that the same will happen in other MPN with specific genetic alterations: polycythemia vera (JAK2 V617F and other JAK2 mutations), essential thrombocythemia (JAK2V617F and MPL515 mutations), primary myelofibrosis (JAK2 V617F and MPL515 mutations), systemic mastocytosis (KITD816V and other KIT mutations) and stem cell leukaemia/lymphoma (ZNF198-FGFR1 and other FGFR1 fusion genes). The current review discusses the above listed mutant molecules in the context of their value as drug targets.
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PMID:Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1. 1917 93

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by excessive production of red blood cells. Patients with PV are at a risk of thrombosis, bleeding, and transformation to myelofibrosis or acute myeloid leukemia. Therapy for PV is based on the use of phlebotomy, aspirin, and in high-risk patients, cytoreductive agents such as hydroxyurea. Anecdotal evidence suggests that imatinib mesylate, a selective tyrosine kinase inhibitor of ABL1, ARG, PDGFR, and KIT kinases has activity in PV. We conducted an open-label phase II clinical trial of imatinib at the standard dose of 400 mg daily in 24 patients with PV. The median duration of imatinib therapy was 5.1 months (range 0.2-86.4). Overall, 4 (17%) patients responded: one had a complete and three partial hematological response. The median time to response was 17.5 months (range 6-28), and the median duration of response was 17 months (range 9-68). No significant changes in JAK2(V617F) mutation burden were noted during imatinib therapy when compared with pretreatment values (P = 0.46). Therapy with imatinib was generally well tolerated. Our data indicate that imatinib has minimal clinical activity in PV.
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PMID:Imatinib mesylate therapy for polycythemia vera: final result of a phase II study initiated in 2001. 1948 34

The 2008 WHO classification system for hematological malignancies is comprehensive and includes histology and genetic information. Myeloid neoplasms are now classified into five categories: acute myeloid leukemia, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN, and myeloid and/or lymphoid malignancies associated with eosinophilia and PDGFR or FGFR1 rearrangements. MPN are subclassified into eight separate entities: chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, systemic mastocytosis, chronic eosinophilic leukemia not otherwise specified, chronic neutrophilic leukemia, and unclassifiable MPN. The diagnosis of chronic myelogenous leukemia requires the presence of BCR-ABL1, while its absence is required for all other MPN. Additional MPN-associated molecular markers include mutations of JAK2, MPL, TET2 and KIT. JAK2 V617F is found in most patients with polycythemia vera, essential thrombocythemia, or primary myelofibrosis and is, therefore, useful as a clonal marker in those settings. The diagnostic utility of MPL and TET2 mutations is limited by low mutational frequency. In systemic mastocytosis, presence of KIT D816V is expected but not essential for diagnosis. Chronic eosinophilic leukemia not otherwise specified should be distinguished from both PDGFR-rearranged or FGFR1-rearranged neoplasms and hypereosinophilic syndrome. We discuss histologic, cytogenetic and molecular changes in MPN and illustrate their integration into practical diagnostic algorithms.
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PMID:Myeloproliferative neoplasms: contemporary diagnosis using histology and genetics. 1980 46