title: Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy.
abstract: The identification of somatic activating mutations in JAK2 (refs 1–4) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK–STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors.
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors: Priya
authors: P
authors: Koppikar
authors: Neha
authors: N
authors: Bhagwat
authors: Outi
authors: O
authors: Kilpivaara
authors: Taghi
authors: T
authors: Manshouri
authors: Mazhar
authors: M
authors: Adli
authors: Todd
authors: T
authors: Hricik
authors: Fan
authors: F
authors: Liu
authors: Lindsay M
authors: LM
authors: Saunders
authors: Ann
authors: A
authors: Mullally
authors: Omar
authors: O
authors: Abdel-Wahab
authors: Laura
authors: L
authors: Leung
authors: Abby
authors: A
authors: Weinstein
authors: Sachie
authors: S
authors: Marubayashi
authors: Aviva
authors: A
authors: Goel
authors: Mithat
authors: M
authors: Gönen
authors: Zeev
authors: Z
authors: Estrov
authors: Benjamin L
authors: BL
authors: Ebert
authors: Gabriela
authors: G
authors: Chiosis
authors: Stephen D
authors: SD
authors: Nimer
authors: Bradley E
authors: BE
authors: Bernstein
authors: Srdan
authors: S
authors: Verstovsek
authors: Ross L
authors: RL
authors: Levine
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006098:Granulocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D055503:Protein Multimerization; D034622:RNA Interference; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053634:TYK2 Kinase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D050791:STAT Transcription Factors; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053634:TYK2 Kinase