title: Selective Janus associated kinase 1 inhibition as a therapeutic target in myelofibrosis.
abstract: Hyperactive Janus associated kinase-signal transducers and activators of transcription (JAK-STAT) signaling has been shown to be integral to the pathogenesis of myelofibrosis (MF) regardless of the driver mutational status (JAK2V617F, JAK2 exon 12, MPL515L/K, CALR). Targeting of the JAK-STAT pathway has been the intense focus of therapeutic development and led to the approval of the JAK1/2 inhibitor, ruxolitinib. Despite the clear clinical success of ruxolitinib, dose limiting thrombocytopenia, treatment associated anemia and failure to effectively achieve bone marrow pathologic, cytogenetic and molecular remission remain shortcomings. JAK1 inhibition leads to depression in inflammatory cytokine expression associated with MF-related constitutional symptoms. The selective targeting of JAK1 may provide an opportunity to alleviate MF-related symptoms without anti-JAK2 therapy-related myelosuppression. Additionally, a JAK1 inhibitor may serve as an ideal candidate partner for combination therapeutic approaches in the treatment of MF. Current evaluation of selective JAK1 inhibition in MF will further clarify the relative contribution of aberrant JAK1 signaling to the pathogenesis of MF.
authors.affiliation: a Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: John
authors.initials: J
authors.lastname: Mascarenhas
mesh_terms: D016207:Cytokines / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D053613:Janus Kinase 1
keywords: JAK; Myelofibrosis; cytokines; inhibitor; rationale