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.

Department of Hematology Odense University Hospital Odense Denmark

Department of Hematology Oncology Hemostaseology and Stem Cell Transplantation Faculty of Medicine RWTH Aachen University Aachen Germany

Department of Hematology Zealand University Hospital Copenhagen University Hospital Roskilde Denmark

Department of Internal Medicine Hematology and Oncology Masaryk University and University Hospital Brno Brno Czech Republic

Institute for Computational Genomics Joint Research Center for Computational Biomedicine RWTH Aachen University Aachen Germany

Institute of Biochemistry and Molecular Biology Faculty of Medicine RWTH Aachen University Aachen Germany

Institute of Pathology Faculty of Medicine RWTH Aachen University Aachen Germany

Interdisciplinary Center for Clinical Research Aachen Faculty of Medicine RWTH Aachen University Aachen Germany

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Leukemia. 2020 Apr;34(4):1210-1212. doi: 10.1038/s41375-019-0636-0. PubMed

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