Publication details

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

Authors	CZECH Julia CORDUA Sabrina WEINBERGEROVÁ Barbora BAUMEISTER Julian CREPCIA Assja HAN Lijuan MAIÉ Tiago COSTA Ivan G. DENECKE Bernd MAURER Angela SCHUBERT Claudia FELDBERG Kristina GEZER Deniz BRÜMMENDORF Tim H. MÜLLER-NEWEN Gerhard MAYER Jiří RÁČIL Zdeněk KUBEŠOVÁ Blanka KNUDSEN Trine SORENSEN Anders L. HOLMSTRÖM Morten KJAR Lasse SKOV Vibe LARSEN Thomas S. HASSELBALCH Hans C. CHATAIN Nicolas KOSCHMIEDER Steffen
Year of publication	2019
Type	Article in Periodical
Magazine / Source	Leukemia
MU Faculty or unit	Faculty of Medicine
Citation
Web	https://www.ncbi.nlm.nih.gov/pubmed/30470838
Doi	http://dx.doi.org/10.1038/s41375-018-0295-6
Keywords	Ph negative myeloproliferative disease; JAK2V617F; CALR; interferon alpha; molecular response
Description	Pegylated interferon-alpha (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.