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.
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Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms
Nature Communications Open Access 01 April 2022
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We are grateful for the assistance of the QIMR Berghofer animal house, flow cytometry facility and business development office. We gratefully acknowledge the support of the MPN Research Foundation, MPN Alliance of Australia, CSL Centenary Fellowship, NHMRC, Gordon and Jessie Gilmour Trust, Cure Cancer Australia Foundation (SWL) and Leukaemia Foundation of Australia (SWL and RA). Murine Ropeginterferon-α (mP1101) was a gift from PharmaEssentia.
Conflict of interest
SWL has participated in advisory boards for Novartis. Pegylated murine IFN-α (mP1101) was a gift from Pharmaessentia. FHH has served as a consultant for and has received research funding from Novartis Inc. SJL, NTC, and CWL are employees of PharmaEssentia Co. The other authors declare that they have no conflict of interest.
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Austin, R.J., Straube, J., Bruedigam, C. et al. Distinct effects of ruxolitinib and interferon-alpha on murine JAK2V617F myeloproliferative neoplasm hematopoietic stem cell populations. Leukemia 34, 1075–1089 (2020). https://doi.org/10.1038/s41375-019-0638-y
Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms
Nature Communications (2022)