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Leukemia. 2019 Nov 15. doi: 10.1038/s41375-019-0638-y. [Epub ahead of print]

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

Author information

1
Cancer Program, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, QLD, 3006, Australia.
2
The University of Queensland, St Lucia, QLD, 4072, Australia.
3
Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), 69120, Heidelberg, Germany.
4
PharmaEssentia Co, Taipei, Taiwan.
5
PharmaEssentia, USA, LLC, Burlington, MA, USA.
6
Leibniz-Institute on Aging-Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745, Jena, Germany.
7
Innere Medizin 2, Hämatologie und Onkologie, Universitätsklinikum Jena, 07747, Jena, Germany.
8
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
9
Fred Hutchinson Cancer Centre, Seattle Cancer Care Alliance, Seattle, WA, USA.
10
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
11
Cancer Program, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, QLD, 3006, Australia. megan.bywater@qimrberghofer.edu.au.
12
The University of Queensland, St Lucia, QLD, 4072, Australia. megan.bywater@qimrberghofer.edu.au.
13
Cancer Program, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, QLD, 3006, Australia. steven.lane@qimrberghofer.edu.au.
14
The University of Queensland, St Lucia, QLD, 4072, Australia. steven.lane@qimrberghofer.edu.au.
15
Cancer Care Services, Royal Brisbane and Women's Hospital, Cnr Butterfield St and Bowen Bridge Rd, Herston, QLD, 4029, Australia. steven.lane@qimrberghofer.edu.au.

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.

PMID:
31732720
DOI:
10.1038/s41375-019-0638-y

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