Myeloproliferative neoplasms: JAK2 signaling pathway as a central target for therapy.

Abstract

The discovery of the JAK2V617F mutation followed by the discovery of other genetic abnormalities allowed important progress in the understanding of the pathogenesis and management of myeloproliferative neoplasms (MPN)s. Classical Breakpoint cluster region-Abelson (BCR-ABL)-negative neoplasms include 3 main disorders: essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Genomic studies have shown that these disorders are more heterogeneous than previously thought with 3 main entities corresponding to different gene mutations: the JAK2 disorder, essentially due to JAK2V617F mutation, which includes nearly all PVs and a majority of ETs and PMFs with a continuum between these diseases and the myeloproliferative leukemia (MPL) and calreticulin (CALR) disorders, which include a fraction of ET and PMF. All of these mutations lead to a JAK2 constitutive activation. Murine models either with JAK2V617F or MPLW515L, but also with JAK2 or MPL germ line mutations found in hereditary thrombocytosis, have demonstrated that they are drivers of myeloproliferation. However, the myeloproliferative driver mutation is still unknown in approximately 15% of ET and PMF, but appears to also target the JAK/Signal Transducer and Activator of Transcription (STAT) pathway. However, other mutations in genes involved in epigenetics or splicing also can be present and can predate or follow mutations in signaling. They are involved either in clonal dominance or in phenotypic changes, more particularly in PMF. They can be associated with leukemic progression and might have an important prognostic value such as additional sex comb-like 1 mutations. Despite this heterogeneity, it is tempting to target JAK2 and its signaling for therapy. However in PMF, Adenosine Tri-Phosphate (ATP)-competitive JAK2 inhibitors have shown their interest, but also their important limitations. Thus, other approaches are required, which are discussed in this review.

• Authors: Florence Pasquier, Xenia Cabagnols, Lise Secardin, Isabelle Plo, William Vainchenker
• Journal: Clinical lymphoma, myeloma & leukemia (Clin Lymphoma Myeloma Leuk) Vol. 14 Suppl Pg. S23-35 (Sep 2014) ISSN: 2152-2669 [Electronic] United States
• PMID: 25486952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Janus Kinase 2

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Enzyme Activation
• Humans
• Janus Kinase 2 (genetics, metabolism)
• Molecular Targeted Therapy
• Mutation
• Myeloproliferative Disorders (drug therapy, genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Signal Transduction (drug effects)