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Region Hovedstaden - en del af Københavns Universitetshospital
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JAK2V617F but not CALR mutations confer increased molecular responses to interferon-α via JAK1/STAT1 activation

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  • Julia Czech
  • Sabrina Cordua
  • Barbora Weinbergerova
  • Julian Baumeister
  • Assja Crepcia
  • Lijuan Han
  • Tiago Maié
  • Ivan G. Costa
  • Bernd Denecke
  • Angela Maurer
  • Claudia Schubert
  • Kristina Feldberg
  • Deniz Gezer
  • Tim H. Brümmendorf
  • Gerhard Müller-Newen
  • Jiri Mayer
  • Zdenek Racil
  • Blanka Kubesova
  • Trine Knudsen
  • Anders L. Sørensen
  • Morten Holmström
  • Lasse Kjær
  • Vibe Skov
  • Thomas Stauffer Larsen
  • Hans C. Hasselbalch
  • Nicolas Chatain
  • Steffen Koschmieder
Vis graf over relationer

Pegylated interferon-α (peg-IFNa) treatment induces molecular responses (MR) in patients with myeloproliferative neoplasms (MPNs), including partial MR (PMR) in 30–40% of patients. Here, we compared the efficacy of IFNa treatment in JAK2V617F- vs. calreticulin (CALR)-mutated cells and investigated the mechanisms of differential response. Retrospective analysis of MPN patients treated with peg-IFNa demonstrated that patients harboring the JAK2V617F mutation were more likely to achieve PMR than those with mutated CALR (p = 0.004), while there was no significant difference in hematological response. In vitro experiments confirmed an upregulation of IFN-stimulated genes in JAK2V617F-positive 32D cells as well as patient samples (peripheral blood mononuclear cells and CD34+ hematopoietic stem cells) compared to their CALR-mutated counterparts, and higher IFNa doses were needed to achieve the same IFNa response in CALR− as in JAK2V617F-mutant 32D cells. Additionally, Janus-activated kinase-1 (JAK1) and signal transducers and activators of transcription 1 (STAT1) showed constitutive phosphorylation in JAK2V617F-mutated but not CALR-mutated cells, indicating priming towards an IFNa response. Moreover, IFN-induced growth arrest was counteracted by selective JAK1 inhibition but enhanced by JAK2 inhibition. In conclusion, our data suggest that, clinically, higher doses of IFNa are needed in CALR-mutated vs. JAK2V617F-positive patients and we suggest a model of JAK2V617F-JAK1/STAT1 crosstalk leading to a priming of JAK2V617F-positive cells to IFNa resulting in differential sensitivity.

OriginalsprogEngelsk
TidsskriftLeukemia
Vol/bind33
Udgave nummer4
Sider (fra-til)995-1010
Antal sider16
ISSN0887-6924
DOI
StatusUdgivet - apr. 2019

ID: 56749119