title: JAK2 inhibitors in the treatment of myeloproliferative neoplasms.
abstract: BACKGROUND
  Dysregulation of JAK-STAT signaling is a pathogenetic hallmark of myeloproliferative neoplasms (MPNs) arising from several distinct molecular aberrations, including mutations in JAK2, the thrombopoietin receptor (MPL), mutations in negative regulators of JAK-STAT signaling, such as lymphocyte-specific adapter protein (SH2B3), and epigenetic dysregulation as seen with Suppressor of Cytokine Signaling (SOCS) proteins. In addition, growth factor/cytokine stimulatory events activate JAK-STAT signaling independent of mutations.
  
  
  METHODS
  The various mutations and molecular events activating JAK-STAT signaling in MPNs are reviewed. Detailed inhibitory kinase profiles of the currently developed JAK inhibitors are presented. Clinical trial results for currently developed JAK targeting agents are comprehensively summarized. The limitations of JAK-STAT targeting in MPNs, as well as potential rational combination therapies with JAK2 inhibitors, are discussed.
  
  
  CONCLUSIONS
  Aberrant JAK-STAT signaling is an underlying theme in the pathogenesis of MPNs. While JAK2 inhibitors are active in JAK2V617F and wild-type JAK2 MPNs, JAK2V617F mutation-specific or JAK2-selective inhibitors may possess unique clinical attributes. Complimentary targeting of parallel pathways operating in MPNs may offer novel therapeutic approaches in combination with JAK inhibition. Understanding the intricacies of JAK-STAT pathway activation, including growth factor/cytokine-driven signaling, will open new avenues for therapeutic intervention at known and novel molecular vulnerabilities of MPNs.
authors.affiliation: Mayo Clinic, Hematology, 200 First Street SW, Rochester, MN 55905, USA. Tibes.raoul@mayo.edu
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
authors.forename: James M
authors.initials: JM
authors.lastname: Bogenberger
authors.forename: Holly L
authors.initials: HL
authors.lastname: Geyer
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mesa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019046:Bone Marrow Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D053614:Janus Kinase 2