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JAK2V617F but not CALR mutations confer increased molecular responses to interferon-α via JAK1/STAT1 activation.
- 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.
- Subjects :
- Adult
Aged
Animals
Antiviral Agents pharmacology
Apoptosis
Biomarkers, Tumor genetics
Biomarkers, Tumor metabolism
Cell Proliferation
Female
Follow-Up Studies
Humans
Janus Kinase 1 genetics
Male
Mice
Middle Aged
Myeloproliferative Disorders genetics
Myeloproliferative Disorders metabolism
Myeloproliferative Disorders pathology
Prognosis
Retrospective Studies
STAT1 Transcription Factor genetics
Tumor Cells, Cultured
Calreticulin genetics
Interferon-alpha pharmacology
Janus Kinase 1 metabolism
Janus Kinase 2 genetics
Mutation
Myeloproliferative Disorders drug therapy
STAT1 Transcription Factor metabolism
Subjects
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