HDAC3在肿瘤微环境介导MCL细胞耐药中的作用和机制研究

Mantle cell lymphoma (MCL) is a subtype of B-Cell Non-Hodgkin’s Lymphomas often associated with unfavorable outcome. In spite of these important advances, a fundamental obstacle to improve MCL therapy is the intrinsic characteristic of MCL to relapse and drug resistance. Mounting evidence suggests that dynamic interactions between the lymphoma cell and its microenvironment play a critical role in MCL development and response to therapy.Our studies to date have shown the following: 1.The expression of HDAC3 is up-regulated following adhesion of MCL cells to stromal cells, effect associated with increased survival and acquisition of a drug-resistance phenotype.2.Genetic or pharmacologic inhibition of HDAC3 with isotype-selective inhibitor induced cell apoptosis and overcome stroma-mediated drug resistance due to a novel mechanism involving HDAC3 upregulation. 3. The stromal cells repress miRNAs that maybe targeting HDAC3. Taken together, our studies provide the rationale to pursue an in-depth evaluation of the role of HDAC3 in the resistance of MCL. The following specific aims are therefore proposed: Aim 1：To determine the contribution of HDAC3 in stroma-mediated drug resistance and AKT and STAT3 activation. Aim 2：To define the functional mechanism of miRNAs in stroma-mediated HDAC3 activation. Aim 3：To determine HDAC3 inhibitor RGFP966 can overcome stroma-mediated drug resistance in vivo.The proposal builds on the following existing strengths: (a) enough MCL cases, and a large repository of well-preserved bone marrow samples, (b) an established co-culture model, cell lines and a strong team background for microenvironment study and miRNA regulation and function, and (c) an already established and ongoing collaboration and publications with Dr. Tao’s Laboratory, Moffitt Cancer Center, USA and finally (d) due to the previously study, we have done many work and published related papers. Through capitalization of these advantages, we ultimately will enhance our understanding about molecular determinants in MCL and provide novel therapeutic stratigies..

套细胞淋巴瘤（MCL）是一类严重危害人类健康的恶性疾病，兼具侵袭性和惰性淋巴瘤的双重缺点，对治疗反应差，极易复发耐药。基质微环境和MCL细胞之间的相互作用对该病的耐药起关键作用。但是，基质微环境介导耐药的详尽分子机制目前尚未阐明。我们前期工作发现基质细胞介导MCL细胞HDAC3高表达，并活化STAT3,AKT信号通路，且基质介导一系列可能调控HDAC3的miRNA的异常表达。而抑制HDAC3可抑制STAT3和AKT活化，促进MCL细胞的凋亡。基于此，我们将深入探索HDAC3活化和STAT3，AKT信号通路激活及上述miRNAs异常表达在基质介导MCL细胞耐药中的作用和机制。并进一步明确体内靶向抑制HDAC3是否能克服耐药，产生强大的抗淋巴瘤效应。鉴于前期工作和业已开展的国际合作等优势，本立项以创新性的思路和方法深入探索MCL的耐药机制，并提出新的治疗策略。

淋巴瘤是一类严重危害人类健康的恶性疾病。基质微环境和MCL细胞之间的相互作用对该病的耐药起关键作用。但是，基质微环境介导耐药的详尽分子机制目前尚未阐明。许多组蛋白脱乙酰酶3(HDAC3)抑制剂在临床和临床前已经显示出显著的抗肿瘤活性。 然而，因为不同程度的毒性与它们广泛的抑制作用使其临床应用受到限制。所以选择性 HDAC抑制可能允许抗淋巴瘤活性而没有不良副作用，并可能成为淋巴瘤治疗的新靶点。弥漫大B细胞淋巴瘤(DLBCL)是B细胞非霍奇金氏淋巴瘤的一种亚型，通常与不良结局相关。 尽管取得了重大进展，但 DLBCL治疗的本质特征是复发和耐药，这是提高DLBCL 治疗效果的根本障碍。 最近，我们发现 miRNA-26a/HDAC3在调节生存/凋亡、微环境介导的耐药性和DLBCL 的侵袭性进程中起着关键作用。 到目前为止，我们的研究表明:与基质细胞共培养的DLBCL 细胞系及原代细胞中，miRNA-26a表达下调，HDAC3过表达。这种效应与增加生存率和获得耐药表型有关。HDAC3与同型选择性抑制剂一起抑制基因或药理作用，诱导细胞凋亡，克服基质介导的耐药性，这是由于 HDAC3调控STAT3和AKT信号通路的新机制。HDAC3在DLBCL进程中的功能作用与miRNA-26a抑制有关，可促进DLBCL进程。 此外，我们观察到HDAC3的抑制克服了DLBCL细胞对常规化疗药物阿霉素的耐药性。 此外，我们的结果表明，HDAC3抑制剂联合EZH2抑制剂 Dznep或BIK抑制剂Ibrutinib协同诱导DLBCL细胞系和原代细胞的细胞毒性。总之，这些结果表明miRNA-26a/ HDAC3是一个有希望的治疗靶点，并提示新型HDAC3抑制剂RGFP966在DLBCL中的临床应用。