title: Deregulated JAK/STAT signalling in lymphomagenesis, and its implications for the development of new targeted therapies.
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.
authors.affiliation: University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia. Electronic address: l.scott3@uq.edu.au.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Scott
authors.affiliation: University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia; Department of Haematology, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Maher K
authors.initials: MK
authors.lastname: Gandhi
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001952:Bridged-Ring Compounds / Q000627:therapeutic use; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D009570:Nitriles; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011759:Pyrrolidines / Q000627:therapeutic use; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000627:therapeutic use; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D007527:Isoenzymes; D053614:Janus Kinase 2; D056484:Jumonji Domain-Containing Histone Demethylases; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011759:Pyrrolidines; D050800:STAT6 Transcription Factor; D013449:Sulfonamides; C561234:11-(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; C545606:AZD 1480; C413655:KDM4C protein, human; C494101:STAT6 protein, human; C528327:fedratinib; D000096926:Benzenesulfonamides; C540383:ruxolitinib; C507924:JAK2 protein, human
keywords: JAK inhibitors; JAK2; Lymphoma; STAT signalling