小儿MLL急性淋巴细胞白血病发病中miRNAs/DOT1L介导的表观遗传机制

Pediatric MLL-rearranged acute lymphoblastic leukemia (MLL(+) ALL) is one of the highest risk of subsets of pediatric cancer. Patients with pediatric MLL(+) ALL often suffer poor chemotherapy response and high risk of relapse, which induce low event free survival rate. Therefore, it is of crucial significance for improving survival rate to develop early diagnosis and new treatment methods. Our previous studies found that the expressions of two miRNAs, miR-27a and miR-29b, are significantly lower in bone marrow of MLL(+) ALL patients than MLL(-) ALL patients. More importantly, they both directly target to the histone methyltransferase Dot1L, which is recruited by MLL-fusion protein, implying that dysregulated miRNAs might play important roles in pathogenesis of pediatric MLL-rearranged leukemia. Based on previous findings, in this project, following studies are initiated: (1) To figure out if miR-27a and miR-29b involved in MLL(+) ALL pathogenesis and the regulatory relationships between miRNAs and DOT1L; (2) To investigatet the epigenetic mechanisms of miR-27a/miR-29b/DOT1L mediated in leukemogenesis in MLL(+) ALL in vitro and in vivo and elucidate the pathogenesis of miRNAs in the disease. The study would provide new theoretical basis and therapeutic target for diagnosis and treatment of pediatric MLL(+) ALL.

小儿MLL急性淋巴细胞白血病（pediatric MLL-rearranged acute lymphoblastic leukemia，MLL(+) ALL)是小儿白血病中的高危病种、存活率低。寻找早期诊断与新的治疗方法对提高其治愈率具有重要的意义。我们前期研究发现，miR-27a和miR-29b在MLL(+) ALL病人骨髓细胞中显著低表达，并与MLL融合蛋白特异性招募的甲基化酶DOT1L存在靶向关系，暗示这2个miRNA异常表达及介导的表观遗传机制在小儿MLL白血病中起调控作用。本研究拟在此基础上开展以下研究：(1)验证miRNA在MLL(+) ALL病人中的表达差异及与DOT1L的关系；(2)研究miRNAs在MLL(+) ALL中调控DOT1L所介导的表观遗传机制及对MLL(+) ALL发病的影响。该项目的完成，可为小儿MLL(+) ALL的发病机制提供新的理论依据及潜在治疗靶点

儿童MLL急性淋巴细胞白血病是一类带有MLL基因重排的血液肿瘤。由于带有MLL基因重排的患者（MLL(+)）五年生存率显著低于其它类型，因此对MLL(+) ALL的发病机理的深入研究从而寻找早期诊断与新的治疗方法对有效提高MLL(+) ALL病人的存活率具有重要的意义。本项目通过对100多例临床标本分析，筛选到2个重要的miRNA分子，这2个miRNA调控该疾病发生重要的组蛋白甲基化酶DOT1L, 调控该疾病的发生发展。我们还发现一批lncRNA与MLL基因重排及融合蛋白形成有关,这些lncRNA很可能激活了下游靶基因MEIS1的表达，从而促进了MLL基因重排细胞的增殖并抑制了这些细胞的分化及凋亡，进而参与了MLL基因重排疾病的发生发展。研究结果已分别发表在Human Molecular Genetics、Science Signaling、Journal of Hematology and Oncology等期刊上。该项目研究结果可为小儿MLL(+) ALL的发病机制提供新的理论依据及潜在的治疗靶点