JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo
JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo
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DOI：
10.1182/blood-2013-12-545640
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发表时间：
2014-08-28
期刊：
影响因子：
20.3
通讯作者：
Holyoake, Tessa L.
中科院分区：
文献类型：
--
作者：
Gallipoli, Paolo;Cook, Amy;Holyoake, Tessa L.
慢性粒细胞白血病（CML）干细胞存活不依赖于BCR-ABL蛋白激酶，ABL酪氨酸激酶抑制剂治疗仅治愈少数CML患者，因此突出了对新治疗靶点的需求。Janus激酶（JAK）2/信号转导子和转录激活子（STAT）5通路最近被探索为CML干/祖细胞（SPC）提供假定的存活信号，但结果相互矛盾。我们使用JAK 2抑制剂ruxolitinib（RUX）研究了该途径的作用。我们证明，在临床上可达到的浓度下，与特异性和有效的酪氨酸激酶抑制剂尼洛替尼组合，相对于单独的单一药物，在体外降低了JAK 2/STAT 5通路的活性。这些作用与体外CML SPC凋亡增加和原始静止CML干细胞（包括NOD）减少相关。Cg-Prkdc（scid）IL 2 rg（tm 1 Wjl）/SzJ小鼠细胞再生，由联合处理诱导。在联合治疗中观察到对正常SPC的一定程度的毒性，尽管这与NOD中的成熟B细胞植入有关。Cg-Prkdc（scid）IL 2 rg（tm 1 Wjl）/SzJ小鼠，对原始CD 34（+）细胞的影响极小。这些结果支持JAK 2/STAT 5通路作为CML SPC的相关治疗靶点，并支持目前在临床试验中使用尼洛替尼联合RUX根除CML患者的持续性疾病。
Chronic myeloid leukemia (CML) stem cell survival is not dependent on BCR-ABL protein kinase and treatment with ABL tyrosine kinase inhibitors cures only a minority of CML patients, thus highlighting the need for novel therapeutic targets. The Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 5 pathway has recently been explored for providing putative survival signals to CML stem/progenitor cells (SPCs) with contradictory results. We investigated the role of this pathway using the JAK2 inhibitor, ruxolitinib (RUX). We demonstrated that the combination of RUX, at clinically achievable concentrations, with the specific and potent tyrosine kinase inhibitor nilotinib, reduced the activity of the JAK2/STAT5 pathway in vitro relative to either single agent alone. These effects correlated with increased apoptosis of CML SPCs in vitro and a reduction in primitive quiescent CML stem cells, including NOD. Cg-Prkdc(scid) IL2rg(tm1Wjl)/SzJ mice repopulating cells, induced by combination treatment. A degree of toxicity toward normal SPCs was observed with the combination treatment, although this related to mature B-cell engraftment in NOD. Cg-Prkdc(scid) IL2rg(tm1Wjl)/SzJ mice with minimal effects on primitive CD34(+) cells. These results support the JAK2/STAT5 pathway as a relevant therapeutic target in CML SPCs and endorse the current use of nilotinib in combination with RUX in clinical trials to eradicate persistent disease in CML patients.