Gamma-Secretase Inhibitors review will focus on the latest developments in the molecular

the mainstay of therapy The only potentially curative therapy is allogeneic hematopoietic stem cell transplantation but treatment-related mortality remains high There have been promising results from clinical trials that involve the JAK tyrosine kinase inhibitors Gamma-Secretase Inhibitors TG101384 and INCB018424 but their role in future therapy is yet to be established Despite the optimism it is increasingly apparent that pathogenicity in BCR-ABL1-negative MPN is more complex than for chronic myeloid leukemia and a pathognomonic mutation may not be forthcomingIn 1951 Dameshek1 organized chronic myelogenous leukemia (CML) polycythemia vera (PV) essential thrombocythemia (ET) and primary myelofibrosis (PMF) into an inclusive disease category that he termed °myeloproliferative disorders (MPD) His rationale was based on similarities in the trilineage proliferation of hematopoietic stem cells and disease phenotypes .

The World Health Organization (WHO) first in 2001 and again in 2008 began reclassifying these disorders in light of evolving histologic cytogenetic and molecular information23 The latest iteration replaced the term myeloproliferative disorders with °myeloproliferative neoplasms (MPN) and incorporated systemic mastocytosis chronic eosinophilic ITMN-191 leukemia-not otherwise specified chronic neutrophilic leukemia and MPN-unclassifiable into the existing MPD category The value of cellular markers as a complement to histologic classification was first validated in CML with the discovery of the Philadelphia chromosome4 and the characterization of the oncogenic BCR-ABL1 fusion protein 5-7 In 2005 it was observed that many patients with °classic BCR-ABL1Cnegative MPDs (PV ET and PMF; Figure 1) carried the somatic mutation JAK2V617F8-10 which had important implications for classification diagnosis and potential targeted therapy .

Additional cytogenic and molecular markers have since been characterized and their role continues to evolve Data from the North American Association of Central Cancer tap water Registries and the Surveillance Epidemiology and End Results program have estimated the annual age-adjusted incidence of BCRABL1C negative MPD to be 21 per 100000 with an overall 3-year survival rate of 80%11 This review will focus on the latest developments in the molecular biology diagnosis and treatment of classic BCR-ABL1Cnegative MPNsIn 2005 a series of studies reported that an activating mutation in Janus kinase 2 (JAK2) ª JAK2V617F ª was highly linked to three related blood diseases: polycythaemia vera essential thrombocythaemia and myelofibrosis .


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