基于MIF表达调控的ALL治疗中糖皮质激素抵抗分子机制实验研究

Glucocorticoid could induce specificly cell cycle arrest and apoptosis in lymphocyte, so it is main medicine in The chemotherapy of lymphatic system tumor.But the The chemotherapy drug resistance,especially GC resistence is the major reason of Poor treatment and prognosis. MIF is the only one is believed to negatively regulate the GC anti-inflammatory cytokines, But, it remains unclear what is the regulation mechanism of GC resistance induced by MIF. In our previous studies, applicant demonstrated the new function of transcription factor ICBP90. Found that The CATT immune susceptibility locus of immunoregulatory cytokine macrophage migration inhibitory factor(MIF) could regulate the expression through ICBP90。We still found the interaction between ICBP90 and GR with Co-IP . So we presume that activated GR with GC get in nucleus to elevate MIF expression by binding ICBP90, then result in inceasing expression of MIF downstream cytokines, finally cause GC resistance. In the present study, the applicant would focus on the mechanisn of GC resistance induced by MIF, clarify the pathway and mechanism of the GC resistance specific regulated by MIF, explore the possibility of regulation of MIF as a new target for ALL treatment. This study is significant to reveals the key molecular mechanisms of GC resistance, looking for new strategy of ALL treatment.

糖皮质激素（GC）能特异性地诱导淋巴细胞周期停滞和凋亡，是治疗淋巴系统肿瘤的主要组成药物，但对化疗药物耐药尤其是对GC耐药是导致ALL疗效和预后差的主要原因。MIF是唯一被认为能负向调节GC抗炎作用的细胞因子，但MIF诱导GC抵抗的关键表达调控机制尚不清楚。我们前期研究中发现了转录因子ICBP90可结合到MIF启动子CATT多态性位点（免疫敏感位点）实现对MIF表达调控新途径。通过Co-IP再次创新性发现GR与ICBP90有相互作用。因此我们推测GC活化GR入核后通过结合ICBP90对MIF表达起调控作用，并进一步导致MIF下游炎症和细胞增殖因子表达上调，最终形成GC抵抗。本项目拟在原有基础上进一步研究MIF诱导的GC抵抗的分子机制，阐明MIF特异性调控GC抵抗的途径和机制, 探讨MIF调控作为ALL治疗新靶点的可能性。本研究对揭示GC抵抗的关键分子机制，寻找防治ALL新策略有重要意义。

糖皮质激素（GC）能特异性地诱导淋巴细胞周期停滞和凋亡，是治疗淋巴系统肿瘤及自身免疫性疾病主要组成药物，但对化疗药物耐药尤其是对GC耐药是导致免疫性疾病疗效和预后差的主要原因。MIF是唯一被认为能负向调节GC抗炎作用的细胞因子，但MIF诱导GC抵抗的关键表达调控机制尚不清楚。我们研究中发现了转录因子ICBP90可结合到MIF启动子CATT多态性位点（免疫敏感位点）实现对MIF表达调控新途径。并证实GC活化GR入核后通过结合ICBP90对MIF表达起调控作用，并进一步导致MIF下游炎症和细胞增殖因子表达上调，最终形成GC抵抗。本项目阐明了MIF诱导的GC抵抗的分子机制，MIF特异性调控GC抵抗的途径和机制, 探讨了MIF调控作为免疫抗炎治疗新靶点的可能性。本研究对揭示GC抵抗的关键分子机制，寻找防治自身免疫性疾病新策略有重要意义。