长非编码RNA-ENST00000454595在小儿MLL基因重排急性淋巴细胞白血病中的功能及作用机制

Pediatric MLL-rearranged acute lymphoblastic leukemia (MLL-r ALL) has the characteristics of low cure rate and poor prognosis, which makes its treatment remains confronted with many severe challenges. More and more evidences showed that long non-coding RNA (lncRNA) plays an essential role in prognosis and progression of cancers. To date, there are no reports about the expression and function of lncRNA in pediatric MLL-r ALL. Our previous studies confirmed that the expression of lncRNA-ENST00000454595 is significantly higher in pediatric MLL-r ALL patients than pediatric ALL patients without MLL rearrangement. Results of mRNA microarray and bioinformatics analysis imply the candidate downstream gene mediating the function of lncRNA-ENST00000454595 is its neighboring protein-coding gene MEIS1. Studies showed that MEIS1 expression is important for the progression of MLL-rearranged leukemias. Based on our previous findings, following studies will be initiated in this project: (1) To figure out the association between the expression of lncRNA-ENST00000454595 and the prognosis of pediatric MLL-r ALL patients; (2) To investigate the function of lncRNA-ENST00000454595 and find its potential downstream gene, such as MEIS1, in pediatric MLL-r ALL. This study would reveal the novel pathogenic mechanism of pediatric MLL-r ALL and provide new theoretical basis to discover new potential therapeutic target for treatment of pediatric MLL-r ALL.

小儿MLL基因重排急性淋巴细胞白血病（MLL-r ALL）由于具有治愈率低、预后差等特点而使得其治疗仍然面临严峻挑战。研究表明，长非编码RNA(lncRNA)在癌症的预后和发生过程中发挥着重要角色。目前尚无针对小儿MLL-r ALL中lncRNA的表达及功能研究的报道。我们前期结果证实，lncRNA-ENST00000454595在小儿MLL-r ALL中的表达显著高于无MLL基因重排的ALL，mRNA芯片结果及生物信息学分析提示介导其功能的可能下游基因是邻近编码基因MEIS1。已知MEIS1的表达跟MLL-r ALL的发生密切相关。本课题拟在此基础上研究lncRNA-ENST00000454595与MLL-r ALL患者预后的关系、其在小儿MLL-r ALL中的功能，以及介导其发挥功能的下游基因，如MEIS1，从而揭示MLL-r ALL新的致病机制，为寻找新的治疗靶点提供理论依据。

小儿MLL基因重排急性淋巴细胞白血病（MLL-r ALL）由于具有治愈率低、预后差等特点而使得其治疗仍然面临严峻的挑战。研究表明，长非编码RNA(lncRNA)在癌症的预后和发生过程中发挥着重要的角色。我们的研究表明部分lncRNA以及mRNA在小儿MLL-r ALL及无MLL基因重排的ALL中的表达明显不同，进一步的研究表明，降低某些lncRNA的表达可以有效促进白血病细胞的增殖并抑制其凋亡。结合临床资料发现，某些lncRNA跟小儿ALL患者的预后有着显著的关系。这些结果有助于深入探讨lncRNA作为小儿白血病预后标志物的可能性，并揭示MLL-r ALL新的致病机制，为寻找新的治疗靶点提供理论依据。此外，我们发现miR-99a的表达与小儿白血病治疗前和治疗后显著相关。进一步的研究表明，miR-99a可以促进白血病细胞的增殖，而抑制其的凋亡。荧光双报告实验、Western blot实验以及结合临床样本证实miR-99a的靶基因是CTDSPL和TRIB2，这有助于深入理解小儿白血病的发病机制以及临床新的药物靶标的发现。