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

Authors :
Czech J
Cordua S
Weinbergerova B
Baumeister J
Crepcia A
Han L
Maié T
Costa IG
Denecke B
Maurer A
Schubert C
Feldberg K
Gezer D
Brümmendorf TH
Müller-Newen G
Mayer J
Racil Z
Kubesova B
Knudsen T
Sørensen AL
Holmström M
Kjær L
Skov V
Larsen TS
Hasselbalch HC
Chatain N
Koschmieder S
Source :
Leukemia [Leukemia] 2019 Apr; Vol. 33 (4), pp. 995-1010. Date of Electronic Publication: 2018 Nov 23.
Publication Year :
2019

Abstract

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.

Details

Language :
English
ISSN :
1476-5551
Volume :
33
Issue :
4
Database :
MEDLINE
Journal :
Leukemia
Publication Type :
Academic Journal
Accession number :
30470838
Full Text :
https://doi.org/10.1038/s41375-018-0295-6