皮肤T细胞淋巴瘤中SATB1的表达影响组蛋白去乙酰化酶抑制剂治疗效果的分子机制研究

The therapeutic modalities for advanced stage cutaneous T cell lymphoma (CTCL) are limited. Histone deacetylase inhibitor (HDACi) has become a new treatment option during the past decade. However, only 30% CTCL patients respond to HDACi treatment, according to multiple clinical trials, and currently there is no molecular marker available for predicting the efficacy of HDACi in CTCL patients. In the previous studies from our group, we identified SATB1 aberrancy in a portion of CTCL and characterized its function. We observed heterogeneity in SATB1 expression: SATB1 is highly expressed in the tumorous T cells in 38% CTCL patients, while in 62% CTCL patients, their tumorous T cells are lack of SATB1. In addition, we found that SATB1 positive CTCL cells are resistant to HDACi, while SATB1 negative cells are sensitive to HDACi treatment. SATB1 is a nuclear matrix protein and can regulate chromatin conformation and gene expression via binding to HDAC1/2 and related complex.In the current study, the applicant aims to characterize the relationship between SATB1 expression and the response to HDACi, as well as its underlying molecular mechanism. The working hypothesis is that SATB1 expression, by binding to HDAC1/2, may affect the chromatin accessibility, so as to affect the expression of key downstream genes, which results in resistance to HDACi treatment. Proving this hypothesis will elucidate the therapeutic mechanism of HDACi, and will lead to the development of prognostic markers predicting HDACi response.

进展期皮肤T细胞淋巴瘤(CTCL)治疗手段十分有限。组蛋白去乙酰化酶抑制剂(HDACi)是近年来批准的新型治疗药物，但只对30%患者有效，且尚无方法预测患者疗效。本研究组既往研究发现SATB1蛋白在CTCL疾病进展中起到重要作用，但其表达存在异质性：38%的患者高表达SATB1，而62%的患者不表达SATB1。在CTCL细胞系中我们发现，SATB1的表达量与对HDACi的敏感性呈反比。SATB1是核基质蛋白，可以通过结合HDAC1/2等复合体调节染色质构象，调控基因表达，提示SATB1可能通过表观遗传学机制调控CTCL细胞对HDACi的敏感性。本项目拟利用细胞系、异种移植动物模型及患者队列，阐明SATB1的表达与HDACi治疗效果的关系及分子机制，证实SATB1通过结合HDAC影响染色质开放程度及关键基因表达，影响HDACi敏感性的科学假说，明确HDACi治疗的分子机制，并开发预后预测标记

蕈样肉芽肿(Mycosis Fungoides，MF)是最常见的皮肤T细胞淋巴瘤(Cutaneous T-cell Lymphoma, CTCL)，其病因及发病机制尚不明确。特殊富含AT序列结合蛋白-1（Special AT-rich sequence-binding protein-1, SATB1）是重要的核基质蛋白，在T细胞的发育和分化中发挥重要作用。既往研究显示在Sézary 综合征中，SATB1表达缺失导致肿瘤细胞对凋亡抵抗，SATB1在MF中的表达存在异质性。然而，在MF中，SATB1表达水平与临床病理的关系及其在临床中的应用仍待明确。本研究利用免疫组织化学技术及实时定量PCR（qRT-PCR）在170例MF患者的队列中评价SATB1在MF皮损中的表达水平，分析其临床病理意义，并利用慢病毒在CTCL细胞系中敲减和过表达SATB1以研究SATB1差异表达导致临床病理差异的机制。结果显示，不同患者间的SATB1表达水平差异反映了MF的固有异质性。SATB1高表达的MF皮损表皮增生及嗜酸性粒细胞浸润显著，且大细胞转化发生率低，SATB1是MF预后良好的分子标记；SATB1与CD30在肿瘤细胞上共表达有助于继发于MF的CD30阳性淋巴细胞增殖性疾病与CD30阳性的大细胞转化的MF间的鉴别诊断，因此SATB1是重要的鉴别诊断标记；SATB1通过正向调控IL-13进而促进MF皮损中的嗜酸性粒细胞浸润，负向调控促进细胞周期进展的基因；在MF皮损中，SATB1与PD-1表达水平负相关；TLR介导的固有免疫活化可能参与了SATB1高表达的MF的发病。SATB1阳性的MF患者可能具有独特的发病机制，提示SATB1可作为一个新的预后、鉴别诊断标记和潜在治疗靶点。