Abstract:
: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.
journal_name
Leukemiajournal_title
Leukemiaauthors
Austin RJ,Straube J,Bruedigam C,Pali G,Jacquelin S,Vu T,Green J,Gräsel J,Lansink L,Cooper L,Lee SJ,Chen NT,Lee CW,Haque A,Heidel FH,D'Andrea R,Hill GR,Mullally A,Milsom MD,Bywater M,Lane SWdoi
10.1038/s41375-019-0638-ysubject
Has Abstractpub_date
2020-04-01 00:00:00pages
1075-1089issue
4eissn
0887-6924issn
1476-5551pii
10.1038/s41375-019-0638-yjournal_volume
34pub_type
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