Abstract
Gene expression profiling has implicated several intracellular signalling cascades, including the JAK/STAT pathway, in the pathogenesis of particular subtypes of lymphoma. In marked contrast to the situation in patients with either acute lymphoblastic leukaemia or a myeloproliferative neoplasm, JAK2 coding sequence mutations are rare in lymphoma patients with an activated JAK/STAT "signature". This is instead the consequence of mutational events that result in the increased expression of non-mutated JAK2; positively or negatively affect the activity of other components of the JAK/STAT pathway; or establish an autocrine signalling loop that drives JAK-mediated cytokine-independent proliferation. Here, we detail these genetic lesions, their functional consequences, and impact on patient outcome. In light of the approval of a JAK1/JAK2 inhibitor for the treatment of myelofibrosis, and preliminary studies evaluating the efficacy of other JAK inhibitors, the therapeutic potential of compounds that target JAK/STAT signalling in the treatment of patients with lymphoma is also discussed.
Keywords:
JAK inhibitors; JAK2; Lymphoma; STAT signalling.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Antineoplastic Agents / therapeutic use*
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Bridged-Ring Compounds / therapeutic use
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Carcinogenesis / drug effects
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Carcinogenesis / genetics
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Gene Expression Regulation, Neoplastic*
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Humans
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Janus Kinase 2 / antagonists & inhibitors*
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Janus Kinase 2 / genetics
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Janus Kinase 2 / metabolism
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Jumonji Domain-Containing Histone Demethylases / genetics
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Jumonji Domain-Containing Histone Demethylases / metabolism
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Lymphoma / drug therapy*
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Lymphoma / genetics
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Lymphoma / metabolism
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Lymphoma / pathology
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Molecular Targeted Therapy
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Nitriles
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Protein Kinase Inhibitors / therapeutic use*
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Pyrazoles / therapeutic use
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Pyrimidines / therapeutic use
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Pyrrolidines / therapeutic use
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STAT6 Transcription Factor / genetics
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STAT6 Transcription Factor / metabolism
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Signal Transduction / drug effects*
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Sulfonamides / therapeutic use
Substances
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11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
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AZD 1480
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Antineoplastic Agents
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Bridged-Ring Compounds
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Isoenzymes
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KDM4C protein, human
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Nitriles
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Pyrrolidines
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STAT6 Transcription Factor
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STAT6 protein, human
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Sulfonamides
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fedratinib
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ruxolitinib
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Jumonji Domain-Containing Histone Demethylases
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JAK2 protein, human
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Janus Kinase 2