azd-1480 and Lymphoma

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.

Topics: Antineoplastic Agents; Bridged-Ring Compounds; Carcinogenesis; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Janus Kinase 2; Jumonji Domain-Containing Histone Demethylases; Lymphoma; Molecular Targeted Therapy; Nitriles; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrrolidines; Signal Transduction; STAT6 Transcription Factor; Sulfonamides