Distinct effects of ruxolitinib and interferon-alpha on murine JAK2V617F myeloproliferative neoplasm hematopoietic stem cell populations.
Distinct effects of ruxolitinib and interferon-alpha on murine JAK2V617F myeloproliferative neoplasm hematopoietic stem cell populations.
复制标题
DOI：
10.1038/s41375-019-0638-y
复制
发表时间：
2020-04
期刊：
影响因子：
11.4
通讯作者：
Lane, Steven W.
中科院分区：
文献类型：
--
作者：
Austin, Rebecca J.;Straube, Jasmin;Bruedigam, Claudia;Pali, Gabor;Jacquelin, Sebastien;Vu, Therese;Green, Joanne;Graesel, Julius;Lansink, Lianne;Cooper, Leanne;Lee, Shin-Jye;Chen, Nien-Tsu;Lee, Chung-Wei;Haque, Ashraful;Heidel, Florian H.;D'Andrea, Richard;Hill, Geoff R.;Mullally, Ann;Milsom, Michael D.;Bywater, Megan;Lane, Steven W.
JAK 2 V617 F是BCR-ABL阴性骨髓增生性肿瘤（MPN）患者中最常见的突变。JAK 2 V617 F造血干细胞（HSC）的根除对于实现分子缓解和治愈至关重要。我们研究了两种治疗方法，ruxolitinib（JAK 1/2抑制剂）和干扰素-α（IFN-α），对疾病引发的HSC人群的不同影响。尽管鲁索利替尼抑制红系祖细胞群体中的Stat 5激活，但它未能抑制HSC中的相同途径。相反，IFN-α对HSC具有直接作用。此外，在Jak 2 V617 F小鼠HSC中，IFN-α刺激后STAT 1磷酸化和途径活化更大，慢性IFN-α治疗后活性氧物质诱导增加，DNA损伤和静止减少。有趣的是，ruxolitinib在体内不阻断IFN-α诱导的Jak 2 V617 F小鼠HSC中的活性氧和DNA损伤。这项工作提供了一个机制原理，告知聚乙二醇化IFN-α如何在临床环境中降低JAK 2 V617 F等位基因负荷，并可能为将来联合收割机鲁索替尼与聚乙二醇化IFN-α联合治疗MPN患者的临床工作提供信息。
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.
登录
查看更多内容
影响因子：
20.3
作者：
Bhagwat, Neha;Koppikar, Priya;Levine, Ross L.
通讯作者：
Levine, Ross L.
影响因子：
20.3
作者：
Kiladjian, Jean-Jacques;Cassinat, Bruno;Fenaux, Pierre
通讯作者：
Fenaux, Pierre
影响因子：
20.3
作者：
Chu, Su;McDonald, Tinisha;Bhatia, Ravi
通讯作者：
Bhatia, Ravi
DOI：
10.1073/pnas.1401873111
发表时间：
2014-10-21
影响因子：
11.1
作者：
Chen, Edwin;Ahn, Jong Sook;Green, Anthony R.
通讯作者：
Green, Anthony R.
影响因子：
11.4
作者：
Harrison CN;Vannucchi AM;Kiladjian JJ;Al-Ali HK;Gisslinger H;Knoops L;Cervantes F;Jones MM;Sun K;McQuitty M;Stalbovskaya V;Gopalakrishna P;Barbui T
通讯作者：
Barbui T