急性T淋巴细胞性白血病(T-ALL)恶性增殖的机制不明和靶向性药物的缺乏是其生存率无法提高的关键因素。靶向维甲酸(RA)通路的药物已成功应用于急性早幼粒白血病的临床治疗，但因RA无法有效激动其受体RARα，其在T-ALL中的进展十分缓慢。前期研究发现，RARα的低磷酸化可以配体非依赖性的方式显著抑制T-ALL增殖，介导周期阻滞相关靶基因的激活并诱导细胞凋亡。基于此，本课题将进一步明确RARα磷酸化水平与T-ALL增殖/凋亡的相关性及相应分子机制，探索以CDK7为代表的激酶对RARα磷酸化的调控作用，并寻找其余潜在的磷酸激酶。通过本课题的研究，不仅将阐明RARα低磷酸化发挥抗T-ALL作用的全新分子机制，探索通过干预RARα磷酸化或上游磷酸激酶治疗T-ALL 的可行性，并为设计基于模拟RARα低磷酸化作用的小分子化合物，或开发以RARα磷酸激酶为潜在靶点的抗白血病药物提供崭新思路和理论依据。

The lack of target therapy and a clear understanding of the mechanisms underlying the aggressive proliferation of T-cell acute lymphoblastic leukemia (T-ALL) is the key factors limiting the survival rate of patients. Therapies targeting the retinoic acid (RA) signaling pathway has been clinically implied in treatment of acute promyelocytic leukemia subtypes, whereas the progress in T-ALL subtypes has been very slow, possibly due to the inactivation of RA receptor RARα in T-ALL. Our previous study found that hypophosphorylation of RA receptor RARα can significantly inhibit the proliferation of T-ALL, accompanied by cell apoptosis and the transcriptional activation of RA-target genes regulating cell cycle arrest. Therefore, this study will further explore the relation between RARα phosphorylation and T-ALL proliferation/apoptosis, clarify possible mechanisms underlying RARα hypophosphorylation-mediated transcriptional activation of downstream target genes and anti-proliferation of leukemic cells, as well as identify potential RARα phosphorylases such as CDK7. Our study not only will clarify the molecular mechanisms of RARα phosphorylation in regulating T-ALL proliferation, but also explore the feasibility of treating T-ALL by targeting RARα phosphorylation or upstream phosphorylases, therefore providing potential targets and theoretical basis for the design and development of anti-leukemia drugs.