Developing MLN8237 as a therapeutic agent for myeloproliferative neoplasms

Project: Research project

Description

Myeloproliferative neoplasms (MPNs) comprise a group of clonal hematological malignancies that include polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF)(1). Although the clonal, stem cell origin of these diseases was established more than 3 decades ago(2), the genetic basis of BCR-ABL–negative MPN remained elusive until several groups identified a somatic activating mutation in the JAK2 kinase (JAK2V617F) in the vast majority of patients with PV and in approximately 50% of ET and PMF patients(3-7). Subsequent studies have identified somatic mutations in the thrombopoietin receptor (MPLW515L/K/A, MPLS505N) in a subset of JAK2V617F-negative ET and PMF, respectively(8-10). Expression of JAK2/MPL mutations in vitro results in constitutive activation of signaling pathways downstream of JAK2, including the STAT3/5, MAP kinase, and PI3K signal transduction pathways(3, 11, 12). Most importantly, expression of JAK2 or MPL mutations in vivo results in fully penetrant myeloproliferation, notable for polycythemia (JAK2V617F) and/or thrombocytosis/myelofibrosis (JAK2V617F, MPLW515L)(8, 12-15).
StatusFinished
Effective start/end date1/1/1312/31/13

Funding

  • Northwestern Memorial Foundation (Agreement Date: 12/20/12)

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Thrombocytosis
Primary Myelofibrosis
Polycythemia Vera
Mutation
Neoplasms
Phosphotransferases
Thrombopoietin Receptors
Polycythemia
Hematologic Neoplasms
Therapeutics
Phosphatidylinositol 3-Kinases
Signal Transduction
Stem Cells
MLN 8237