JAK2V617F but not CALR mutations confer increased molecular responses to interferon-α via JAK1/STAT1 activation

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 SørensenMorten Holmström, Lasse Kjær, Vibe Skov, Thomas Stauffer Larsen, Hans C Hasselbalch, Nicolas Chatain, Steffen Koschmieder*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftArtikelForskningpeer review


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.

Sider (fra-til)995-1010
Antal sider16
Udgave nummer4
StatusUdgivet - apr. 2019


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