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

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

Leukemia

journal_title

Leukemia

authors

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 SW

doi

10.1038/s41375-019-0638-y

subject

Has Abstract

pub_date

2020-04-01 00:00:00

pages

1075-1089

issue

4

eissn

0887-6924

issn

1476-5551

pii

10.1038/s41375-019-0638-y

journal_volume

34

pub_type

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