Epigenetic dysregulation of ZEB1 is involved in LMO2-promoted T-cell acute lymphoblastic leukaemia leukaemogenesis
Epigenetic dysregulation of ZEB1 is involved in LMO2-promoted T-cell acute lymphoblastic leukaemia leukaemogenesis
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ZEB1的表观遗传失调参与LMO2促进的T细胞急性淋巴细胞白血病白血病发生
DOI：
10.1016/j.bbadis.2018.05.013
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发表时间：
2018-08-01
影响因子：
6.2
通讯作者：
Yang，Shuang
中科院分区：
文献类型：
--
作者：
Wu，Chao;Li，Jianjun;Yang，Shuang
T细胞急性淋巴细胞白血病（T-ALL）是一种血液恶性肿瘤，由影响T细胞发育的基因组病变累积引起。ZEB 1是锌指同源结构域家族转录因子，在促进T细胞分化中发挥重要作用，并可能在T-ALL中作为肿瘤抑制因子发挥作用。然而，ZEB 1调节T-ALL白血病发生的分子机制仍然不清楚。在这里，我们发现致癌LIM only 2（LMO 2）可以招募Sap 18和HDAC 1组装表观遗传调控复合物，从而诱导ZEB 1启动子中的组蛋白脱乙酰化和染色质重塑，以实现转录抑制。此外，LMO 2复合物下调ZEB 1导致白血病干细胞（LSC）表型增加以及T-ALL细胞对甲氨蝶呤（MTX）化疗反应不敏感。重要的是，我们证明了曲古抑菌素A（TSA，HDAC抑制剂）的加入显着减弱MTX不敏感性所造成的LMO 2/ZEB 1信号转导功能障碍。总之，这些发现已经确定了LMO 2/ZEB 1介导的白血病发生的分子机制，为用表观遗传抑制剂的新策略治疗T-ALL铺平了道路。
T-cell acute lymphoblastic leukaemia (T-ALL) is a hematological malignancy caused by the accumulation of genomic lesions that affect the development of T-cells. ZEB1, a member of zinc finger-homeodomain family transcription factor, exhibits crucial function in promoting T-cell differentiation and potentially acts as a tumor suppressor in T-ALL. However, the molecular mechanism by which ZEB1 regulates T-ALL leukaemogenesis remains obscure. Here, we showed that oncogenic LIM only 2 (LMO2) could recruit Sap18 and HDAC1 to assemble an epigenetic regulatory complex, thus inducing histone deacetylation in ZEB1 promoter and chromatin remodeling to achieve transcriptional repression. Furthermore, downregulation of ZEB1 by LMO2 complex results in an increased leukaemia stem cell (LSC) phenotype as well as unsensitivity in response to methotrexate (MTX) chemotherapy in T-ALL cells. Importantly, we demonstrated that Trichostatin A (TSA, a HDAC inhibitor) addition significantly attenuates MTX unsensitivity caused by dysfunction of LMO2/ZEB1 signaling. In conclusion, these findings have identified a molecular mechanism underlying LMO2/ZEB1-mediated leukaemogenesis, paving a way for treating T-ALL with a new strategy of epigenetic inhibitors.