Distinct effects of ruxolitinib and interferon-alpha on murine JAK2V617F myeloproliferative neoplasm hematopoietic stem cell populations

• Published in: Leukemia Vol. 34; no. 4; pp. 1075 - 1089
• Main Authors: Austin, Rebecca J., Straube, Jasmin, Bruedigam, Claudia, Pali, Gabor, Jacquelin, Sebastien, Vu, Therese, Green, Joanne, Gräsel, Julius, Lansink, Lianne, Cooper, Leanne, Lee, Shin-Jye, Chen, Nien-Tsu, Lee, Chung-Wei, Haque, Ashraful, Heidel, Florian H., D’Andrea, Richard, Hill, Geoff R., Mullally, Ann, Milsom, Michael D., Bywater, Megan, Lane, Steven W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2020; Nature Publishing Group
• Subjects: 13/100; 13/21; 13/31; 13/95; 42/34; 42/35; 42/41; 631/67/71; 64/60; 692/308/2778; Abl protein; Activation; Animals; Antiviral Agents - pharmacology; BCR protein; Cancer Research; Care and treatment; Cell Proliferation; Cells, Cultured; Critical Care Medicine; Damage; Deoxyribonucleic acid; Development and progression; DNA; DNA damage; Drug Therapy, Combination; Female; Fusion protein; Gene mutations; Genetic aspects; Health aspects; Hematology; Hematopoietic stem cells; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Inhibitor drugs; Intensive; Interferon; Interferon-alpha - pharmacology; Internal Medicine; Janus kinase; Janus Kinase 2 - genetics; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Myeloproliferative disorders; Myeloproliferative Disorders - drug therapy; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - pathology; Neoplasms; Oncology; Patient outcomes; Patients; Phosphorylation; Populations; Pyrazoles - pharmacology; Reactive oxygen species; Stat1 protein; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Stat5 protein; Stem cell transplantation; Stem cells; α-Interferon; Australia
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-019-0638-y

JAK2V617F is the most common mutation in patients with BCR-ABL negative myeloproliferative neoplasms (MPNs). The eradication of JAK2V617F hematopoietic stem cells (HSCs) is critical for achieving molecular remissions and cure. We investigate the distinct effects of two therapies, ruxolitinib (JAK1/2 inhibitor) and interferon-alpha (IFN-α), on the disease-initiating HSC population. Whereas ruxolitinib inhibits Stat5 activation in erythroid progenitor populations, it fails to inhibit this same pathway in HSCs. In contrast, IFN-α has direct effects on HSCs. Furthermore, STAT1 phosphorylation and pathway activation is greater after IFN-α stimulation in Jak2V617F murine HSCs with increased induction of reactive oxygen species, DNA damage and reduction in quiescence after chronic IFN-α treatment. Interestingly, ruxolitinib does not block IFN-α induced reactive oxygen species and DNA damage in Jak2V617F murine HSCs in vivo. This work provides a mechanistic rationale informing how pegylated IFN-α reduces JAK2V617F allelic burden in the clinical setting and may inform future clinical efforts to combine ruxolitinib with pegylated IFN-α in patients with MPN.