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

Autor: Czech, Julia, Cordua, Sabrina, Weinbergerova, 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, Jiri, Racil, Zdenek, Kubesova, Blanka, Knudsen, Trine, Sørensen, Anders L., Holmström, Morten, Kjær, Lasse, Skov, Vibe, Larsen, Thomas Stauffer, Hasselbalch, Hans C., Chatain, Nicolas, Koschmieder, Steffen
Zdroj: Leukemia; April 2019, Vol. 33 Issue: 4 p995-1010, 16p
Abstrakt: 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
Databáze: Supplemental Index
Externí odkaz: