| First Author | Austin RJ | Year | 2020 |
| Journal | Leukemia | Volume | 34 |
| Issue | 4 | Pages | 1075-1089 |
| PubMed ID | 31732720 | Mgi Jnum | J:290132 |
| Mgi Id | MGI:6404308 | Doi | 10.1038/s41375-019-0638-y |
| Citation | Austin RJ, et al. (2020) Distinct effects of ruxolitinib and interferon-alpha on murine JAK2V617F myeloproliferative neoplasm hematopoietic stem cell populations. Leukemia 34(4):1075-1089 |
| abstractText | 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-alpha), 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-alpha has direct effects on HSCs. Furthermore, STAT1 phosphorylation and pathway activation is greater after IFN-alpha stimulation in Jak2V617F murine HSCs with increased induction of reactive oxygen species, DNA damage and reduction in quiescence after chronic IFN-alpha treatment. Interestingly, ruxolitinib does not block IFN-alpha induced reactive oxygen species and DNA damage in Jak2V617F murine HSCs in vivo. This work provides a mechanistic rationale informing how pegylated IFN-alpha reduces JAK2V617F allelic burden in the clinical setting and may inform future clinical efforts to combine ruxolitinib with pegylated IFN-alpha in patients with MPN. |
