BCR-ABL-Induced Deregulation of the IL-33/ST2 Pathway in CD34(+) Progenitors from Chronic Myeloid Leukemia Patients
BCR-ABL-Induced Deregulation of the IL-33/ST2 Pathway in CD34(+) Progenitors from Chronic Myeloid Leukemia Patients
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DOI：
10.1158/0008-5472.can-13-2797
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发表时间：
2014-05-15
期刊：
影响因子：
11.2
通讯作者：
Herbelin, Andre
中科院分区：
文献类型：
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作者：
Levescot, Anais;Flamant, Stephane;Herbelin, Andre
虽然人们普遍认为细胞因子以自分泌/旁分泌的方式调节正常的造血，但它们在慢性粒细胞白血病(CML)和甲磺酸伊马替尼耐药中的可能作用仍未得到充分研究。在这里，我们报告了慢性粒细胞白血病患者确诊时CD34(+)祖细胞被细胞因子/丙氨酸白介素33选择性靶向。事实上，CML CD34(+)祖细胞上调其细胞表面IL-33特异性受体链ST2的表达，增殖并产生细胞因子，以响应IL-33，反之，来自健康个体的CD34(+)细胞。此外，在伊马替尼治疗后，ST2的过度表达被正常化，而IL-33在体外通过重新激活STAT5通路来对抗伊马替尼诱导的CML CD34(+)祖细胞的生长停滞，从而支持IL-33可能阻碍了伊马替尼对CML CD34(+)祖细胞的抗增殖作用。在临床上，循环中的可溶性ST2水平通常被认为是体内IL-33信号的功能标志，与疾病负担相关。事实上，这些升高的外周血药浓度与预测治疗结果的高Sokal评分相关，在分子缓解期患者中是正常的。最后，通过对免疫缺陷NOG小鼠的异种移植实验，我们证明了IL-33对CML患者CD34(+)祖细胞体内维持的促进作用，并且我们发现在IL-33缺陷小鼠中，BCR-ABL转基因小鼠骨髓前体细胞的植入效率低于野生型受体。综上所述，我们的结果提供了证据，IL-33/ST2信号可能代表了一种新的细胞因子介导的促进CML前体细胞生长的机制，并支持该途径在CML维持和甲磺酸伊马替尼耐药中的作用。(C)2014年AACR。
Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myelogenous leukemia (CML) and resistance to imatinib mesylate treatment remain poorly investigated. Here, we report that CD34(+) progenitors from patients with CML at diagnosis are selectively targeted by the cytokine/alarmin interleukin (IL)-33. Indeed, CML CD34(+) progenitors upregulate their cell surface expression of the IL-33-specific receptor chain ST2, proliferate and produce cytokines in response to IL-33, conversely to CD34(+) cells from healthy individuals. Moreover, ST2 overexpression is normalized following imatinib mesylate therapy, whereas IL-33 counteracts in vitro imatinib mesylate-induced growth arrest in CML CD34(+) progenitors via reactivation of the STAT5 pathway, thus supporting the notion that IL-33 may impede the antiproliferative effects of imatinib mesylate on CD34(+) progenitors in CML. Clinically, the levels of circulating soluble ST2, commonly considered a functional signature of IL-33 signaling in vivo, correlate with disease burden. Indeed, these elevated peripheral concentrations associated with a high Sokal score predictive of therapeutic outcome are normalized in patients in molecular remission. Finally, we evidenced a facilitating effect of IL-33 on in vivo maintenance of CD34(+) progenitors from patients with CML by using xenotransplant experiments in immunodeficient NOG mice, and we showed that engraftment of mouse BCR-ABL-transfected bone marrow progenitors was less efficient in IL-33-deficient mice compared with wild-type recipients. Taken together, our results provide evidence that IL-33/ST2 signaling may represent a novel cytokine-mediated mechanism contributing to CML progenitor growth and support a role for this pathway in CML maintenance and imatinib mesylate resistance. (C) 2014 AACR.