The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia.
The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia.
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DOI：
10.18632/oncotarget.4212
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发表时间：
2015-09-08
期刊：
影响因子：
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通讯作者：
Colomer D
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文献类型：
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作者：
Xargay-Torrent S;López-Guerra M;Rosich L;Montraveta A;Roldán J;Rodríguez V;Villamor N;Aymerich M;Lagisetti C;Webb TR;López-Otín C;Campo E;Colomer D
剪接体组分的突变或表达失调可以影响几种基因的剪接模式并有助于肿瘤的发展。在这种情况下，我们报告说，剪接体调节剂sudemycin诱导选择性细胞毒性在原发性慢性淋巴细胞白血病（CLL）细胞相比，健康的淋巴细胞和肿瘤细胞从其他B淋巴恶性肿瘤，与CLL的情况下有轻微的偏差突变剪接体RNA加工机械。因此，在移植了CLL患者原代细胞的NOD/SCID/IL 2 R γ−/−（NSG）小鼠中，sudemycin表现出相当大的抗肿瘤活性。苏德霉素的抗白血病作用涉及剪接调制的几个靶基因的肿瘤生存的重要性，无论是在SF 3B 1突变和非突变的情况下。因此，该化合物诱导的细胞凋亡与MCL 1向其促凋亡亚型的选择性剪接开关有关。苏得霉素还在功能上干扰NF-κB途径，同时诱导剪接的RELA变体，该变体失去其DNA结合结构域。重要的是，我们显示了苏地霉素与伊曲替尼组合的增强的抗肿瘤作用，这可能与Btk抑制剂（IBTK）的选择性剪接的调节有关。总之，我们提供了剪接体是CLL中相关治疗靶点的第一个证据，支持单独使用剪接调节剂或与伊曲替尼联合使用剪接调节剂作为治疗CLL患者的有希望的方法。
Mutations or deregulated expression of the components of the spliceosome can influence the splicing pattern of several genes and contribute to the development of tumors. In this context, we report that the spliceosome modulator sudemycin induces selective cytotoxicity in primary chronic lymphocytic leukemia (CLL) cells when compared with healthy lymphocytes and tumor cells from other B-lymphoid malignancies, with a slight bias for CLL cases with mutations in spliceosome-RNA processing machinery. Consistently, sudemycin exhibits considerable antitumor activity in NOD/SCID/IL2Rγ−/− (NSG) mice engrafted with primary cells from CLL patients. The antileukemic effect of sudemycin involves the splicing modulation of several target genes important for tumor survival, both in SF3B1-mutated and -unmutated cases. Thus, the apoptosis induced by this compound is related to the alternative splicing switch of MCL1 toward its proapoptotic isoform. Sudemycin also functionally disturbs NF-κB pathway in parallel with the induction of a spliced RELA variant that loses its DNA binding domain. Importantly, we show an enhanced antitumor effect of sudemycin in combination with ibrutinib that might be related to the modulation of the alternative splicing of the inhibitor of Btk (IBTK). In conclusion, we provide first evidence that the spliceosome is a relevant therapeutic target in CLL, supporting the use of splicing modulators alone or in combination with ibrutinib as a promising approach for the treatment of CLL patients.