BCR-ABL activity is critical for the immunogenicity of chronic myelogenous leukemia cells
BCR-ABL activity is critical for the immunogenicity of chronic myelogenous leukemia cells
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DOI：
10.1158/0008-5472.can-07-0302
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发表时间：
2007-06-01
期刊：
影响因子：
11.2
通讯作者：
Brossart, Peter
中科院分区：
文献类型：
--
作者：
Brauer, Katharina M.;Werth, Daniela;Brossart, Peter
慢性粒细胞白血病（CML）是一种由组成型活性酪氨酸激酶BCR-ABL形成的过度粒细胞生成引起的粒细胞增殖性疾病。甲磺酸伊马替尼是一种有效的抗CML药物，它是一种酪氨酸激酶抑制剂，作用于Abl激酶、c-KIT和血小板衍生生长因子受体。最近，一项研究显示，与ifn - α治疗的患者相比，伊马替尼治疗的患者CTL反应受损，这可能是由于治疗诱导的CML细胞免疫原性降低或免疫抑制作用。在我们的研究中，我们发现抑制BCR-ABL导致伊马替尼治疗后CML细胞免疫原性抗原下调，从而抑制CML导向的免疫应答。通过用伊马替尼治疗CML细胞，我们可以证明BCR-ABL的抑制导致肿瘤抗原的表达降低，包括survivin、adipophilin、hTERT、WT-1、Bcl-x(L)和Bcl-2，这些抗原与CML特异性ctl的减少有关。相比之下，当使用抗伊马替尼抑制作用的CML细胞系时，没有观察到这种免疫原性的降低，但可以通过转染针对BCR-ABL的特异性小干扰RNA或伊马替尼治疗原代CML细胞来证实。
Chronic myclogenous leukemia (CML) is a mycloprotiferative disorder caused by excessive granulopoiesis due to the formation of the constitutively active tyrosine kinase BCR-ABL. An effective drug against CML is imatinib mesylate, a tyrosine kinase inhibitor acting on Abl kinases, c-KIT, and platelet-derived growth factor receptor. Recently, a study revealed that patients treated with imatinib showed impaired CTL responses compared with patients treated with IFN-alpha, which might be due to a treatment-induced reduction in immunogenicity of CML cells or immunosuppressive effects. In our study, we found that inhibition of BCR-ABL leads to a down-regulation of immunogenic antigens on the CML cells in response to imatinib treatment, which results in the inhibition of CML-directed immune responses. By treating CML cells with imatinib, we could show that the resulting inhibition of BCR-ABL leads to a decreased expression of tumor antigens, including survivin, adipophilin, hTERT, WT-1, Bcl-x(L), and Bcl-2 in correlation to a decreased development of CML-specific CTLs. In contrast, this reduction in immunogenicity was not observed when a CML cell line resistant to the inhibitory effects of imatinib was used, but could be confirmed by transfection with specific small interfering RNA against BCR-ABL or imatinib treatment of primary CML cells.