β-arrestin1调控组蛋白H3修饰增强Tal1表达促进急性T淋巴细胞白血病细胞增殖的机制研究

Leukemia is the most common malignant tumor in children, and acute lymphoblastic leukemia (ALL) is the main type of childhood leukemia, which is classified into acute B lymphoblastic leukemia (B-ALL) and acute T lymphoblastic leukemia (T-ALL). Among them, T-ALL is with high degree of malignancy, low disease free survival rate and high recurrence rate. The aberrant transcription factor and histone H3 are key for T-ALL pathogenesis, and its epigenetic regulation is highly concerned. beta-arrestin1, a multiple signal molecule, is a scaffold protein to combine with multiple molecules to regulate cellular transcription. Our team has been focusing on the epigenetic mechanism of beta-arrestin1 in regulating leukemia progress. The recent preliminary results showed that the aberrant increased expression of beta-arrestin1 was observed in T-ALL patients, and beta-arrestin1 regulated the expression of Tal1, the key transcription factor for T-ALL. Here, we continue the previous study, by using T-ALL model in vitro and in vivo, to in-depth explore the epigenetic mechanisms of nuclear beta-arrestin1, in combination with YY1 or EP300, to regulate chromatin histone H3 methylation and/or acetylation, to further enhance Tal expression, and thus to promote T-ALL cell proliferation. This work will illustrate the pathogenesis of refractory T-ALL and lay the foundation for a new epigenetic drug target for leukemia, which has important theoretical significance and potential clinical value.

白血病是儿童最常见的恶性肿瘤，急性淋巴细胞白血病(ALL)是儿童白血病的最主要类型，可分为急性B淋巴细胞白血病(B-ALL)和急性T淋巴细胞白血病(T-ALL)。其中T-ALL恶性程度与复发率高，转录因子异常和组蛋白H3是T-ALL发病的关键因素，其表观遗传调控备受关注。信号分子beta-arrestin1(β-Arr1)能作为支架蛋白结合多分子调控细胞转录。项目组一直致力于β-Arr1调控白血病进程的表观遗传机制研究，近期发现T-ALL中β-Arr1表达异常增高，且调控关键转录因子Tal1表达。本项目延续前期研究，利用体内外T-ALL模型，深入探究核内β-Arr1与YY1或EP300结合，调控染色质组蛋白H3甲基化和/或乙酰化修饰，进而增强Tal1表达，促进T-ALL细胞增殖的表观遗传机制，为阐释难治性白血病发病机制、寻找新型表观遗传药物靶点具有重要意义和潜在的临床价值。

白血病是儿童最常见的恶性肿瘤，急性淋巴细胞白血病（ALL）是儿童白血病的最主要类型，可分为急性B淋巴细胞白血病（B-ALL）和急性T淋巴细胞白血病（T-ALL）。其中T-ALL恶性程度与复发率高，转录因子异常和组蛋白H3是T-ALL发病的关键因素，其表观遗传调控备受关注。重要信号分子beta-arrestin1（β-Arr1）能作为支架蛋白结合多分子调控细胞转录。项目组一直致力于β-Arr1调控白血病进程的表观遗传机制研究，本项目延续前期研究，利用体内外T-ALL模型，发现T-ALL中β-Arr1表达显著减少，减少与E3-泛素化连接酶中的DTX1相互作用，导致T-ALL的驱动分子Notch1降解减少，从而促进其下游基因Hes1表达，抑制凋亡分子表达，促进T-ALL进展；进一步研究发现，T-ALL特异性癌miRNA—miR-223可与β-Arr1 mRNA的3’UTR结合，抑制β-Arr1表达，拮抗T-ALL细胞中miR-223可成功诱导T-ALL细胞凋亡，抑制T-ALL肿瘤进程；在此基础上，设计环状miRNA拮抗片段表达逆转录病毒系统（CimiR系统），证明其在细胞中稳定性强于线性miRNA拮抗片段表达系统后，抑制miR-223与β-Arr1 3’UTR结合，验证了其对T-ALL细胞中癌基因miR-223的拮抗效率。综上所述，本项目从表观遗传角度，经过体内外T-ALL模型，阐释了基于miR-223与β-Arr1的拮抗，可能作为一种新的T-ALL治疗方法奠定了理论与实验基础。