Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms Journal Article

Authors: Bhagwat, N.; Koppikar, P.; Keller, M.; Marubayashi, S.; Shank, K.; Rampal, R.; Qi, J.; Kleppe, M.; Patel, H. J.; Shah, S. K.; Taldone, T.; Bradner, J. E.; Chiosis, G.; Levine, R. L.
Article Title: Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms
Abstract: The discovery of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) led to clinical development of Janus kinase (JAK) inhibitors for treatment of MPN. These inhibitors improve constitutional symptoms and splenomegaly but do not significantly reduce mutant allele burden in patients. We recently showed that chronic exposure to JAK inhibitors results in inhibitor persistence via JAK2 transactivation and persistent JAK - signal transducer and activator of transcription signaling. We performed genetic and pharmacologic studies to determine whether improved JAK2 inhibition would show increased efficacy in MPN models and primary samples. Jak2 deletion in vivo led to profound reduction in disease burden not seen with JAK inhibitors, and deletion of Jak2 following chronic ruxolitinib therapy markedly reduced mutant allele burden. This demonstrates that JAK2 remains an essential target in MPN cells that survive in the setting of chronic JAK inhibition. Combination therapy with the heat shock protein 90 (HSP90) inhibitor PU-H71 and ruxolitinib reduced total and phospho-JAK2 and achieved more potent inhibition of downstream signaling than ruxolitinib monotherapy. Combination treatment improved blood counts, spleen weights, and reduced bone marrow fibrosis compared with ruxolitinib alone. These data suggest alternate approaches that increase JAK2 targeting, including combination JAK/HSP90 inhibitor therapy, are warranted in the clinical setting. © 2014 by The American Society of Hematology.
Keywords: controlled study; myelofibrosis; unclassified drug; janus kinase 2; drug efficacy; monotherapy; nonhuman; drug targeting; animal cell; mouse; animal tissue; animal experiment; animal model; transactivation; heat shock protein 90 inhibitor; pu h71; blood cell count; drug dose increase; myeloproliferative neoplasm; spleen weight; ruxolitinib; priority journal; article
Journal Title: Blood
Volume: 123
Issue: 13
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2014-03-27
Start Page: 2075
End Page: 2083
Language: English
DOI: 10.1182/blood-2014-01-547760
PROVIDER: scopus
PMCID: PMC3968390
PUBMED: 24470592
Notes: Cited By (since 1996):1 -- Export Date: 1 May 2014 -- CODEN: BLOOA -- Source: Scopus
Altmetric Score
MSK Authors
  1. Raajit Kumar Rampal
    125 Rampal
  2. Ross Levine
    463 Levine
  3. Hardik Jitendra Patel
    24 Patel
  4. Gabriela Chiosis
    215 Chiosis
  5. Tony Taldone
    74 Taldone
  6. Neha Bhagwat
    21 Bhagwat
  7. Maria Kleppe
    28 Kleppe
  8. Kaitlyn Ruth Shank
    19 Shank
  9. Smit Kamalkumar Shah
    8 Shah
  10. Matthew D Keller
    23 Keller