IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models
IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models
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DOI：
10.1182/blood-2015-11-679985
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发表时间：
2016-12-08
期刊：
影响因子：
20.3
通讯作者：
Fioretos, Thoas
中科院分区：
文献类型：
--
作者：
Agerstam, Helena;Hansen, Nils;Fioretos, Thoas
慢性粒细胞白血病(CML)目前使用酪氨酸激酶抑制剂治疗，但这些药物并不能有效消除CML干细胞。因此，慢性粒细胞白血病干细胞持续存在，并导致大多数患者在停药后复发。此外，对这种疾病的晚期没有有效的治疗方法。白介素1受体辅助蛋白(IL1RAP；IL1R3)是白介素1受体1型的辅助受体，已发现在CML干细胞上表达上调。在这里，我们发现原始的(CD34(+)CD38(-))CML细胞，与相应的正常细胞相比，表达一个功能性的白介素1(IL-1)受体复合体，并对IL-1做出反应，激活NFkB并显著增殖。抑制IL-1信号的IL1RAP抗体可以阻断这些效应。IL1RAP抗体在移植慢性期和急性期CML细胞的小鼠体内产生了由小鼠效应细胞介导的治疗效应。这些结果为IL1RAP在CML中的作用提供了新的见解，并为开发针对CML残留干细胞的IL1RAP抗体疗法提供了强有力的理论基础。
Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors, but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. Interleukin-1 receptor accessory protein (IL1RAP; IL1R3) is a coreceptor of interleukin-1 receptor type 1 and has been found upregulated onCMLstem cells. Here, we show that primitive (CD34(+) CD38(-)) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NFkB activation and marked proliferation in response to IL-1. IL1RAP antibodies that inhibit IL-1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rationale for the development of an IL1RAP antibody therapy to target residual CML stem cells.