SATB1蛋白在皮肤CD30+淋巴细胞增生性疾病进展中的作用

SATB1 is a tissue-specific nuclear matrix binding protein, which involves in chromatin remodeling and tissue-specific gene expression regulation. In a previous study published by the applicant, deficiency of SATB1 expression in Sézary cells - a leukemia type of cutaneous CD4+ T cell lymphoma, plays an important role in the pathogenesis of Sézary syndrome by causing apoptosis resistance on Sézary cells. Restoration of SATB1 expression activates Fas mediated external apoptosis pathway by regulating FasL expression under T cell receptor activation. Cutaneous CD30+ lymphoproliferative disease consists of lymphomatoid papulosis (LyP), which demonstrated a benign clinical course, and its malignant counterpart - cutaneous anaplastic large cell lymphoma (c-ALCL). Although the skin lesion of LyP is characterized by its spontaneous regression, part of the patients will inevitably progress to c-ALCL despite of aggressive treatments. However, the mechanism of disease progression is still largely unknown. In our recent study, we found that SATB1 is highly expressed in the CD30+ large T cells in LyP, but absent in the malignant CD30+ T cells in c-ALCL, which suggested new clues for the disease progression mechanism. This propsed study will focus on the role of SATB1 expression in the spontaneous regression of LyP and the role of SATB1 repression in disease progression from LyP to c-ALCL. By restoring or knocking-down SATB1 expression in Mac-1 cell line which was derived from a skin lesion of a c-ALCL patient who progressed from LyP, the role of SATB1 expression in cell apoptosis, cell cycle, as well as in vitro/in vivo tumor forming will be observed. Further, the molecular pathway downstream SATB1 will be investigated, in particular Fas mediated apoptosis pathway. This study aims to demonstrate the role of aberrant SATB1 expression in the disease progression of cutaneous CD30+ lymphoproliferative disease and its underlying molecular pathway. SATB1 may serve as a novel molecular target for developing new therapies for c-ALCL, which currently does not have a cure.

SATB1是组织特异性的核基质结合蛋白，参与染色质高级结构的形成和基因的表达调控。本课题组既往的研究中发现SATB1的表达抑制导致恶性的CD4+T细胞对凋亡抵抗，并阐明SATB1的表达通过上调FasL的表达激活Fas及下游的凋亡通路。皮肤CD30+淋巴细胞增生性疾病包括良性的淋巴瘤样丘疹病(LyP)及侵袭性的皮肤间变性大细胞淋巴瘤(c-ALCL)。LyP的皮疹自行消退及其进展到c-ALCL的机制尚不明确。本课题组新近发现SATB1蛋白高表达于LyP皮损中，而不表达于c-ALCL中恶性的CD30+细胞上，为研究提供了新的线索。本研究拟以由LyP进展到c-ALCL的细胞系为研究模型，在其中重建/敲减SATB1的表达，从体外、体内两个层面观察SATB1对细胞凋亡及疾病进展的影响及其下游分子通路，阐明SATB1蛋白的表达差异在皮肤CD30+细胞增生性疾病进展中的作用，为早期控制疾病提供理论基础。

原发皮肤CD30+淋巴增殖性疾病（Primary cutaneous CD30 positive lymphoproliferative disorders, CD30+CLPD）是第二大类皮肤T细胞淋巴瘤（Cutaneous T cell lymphoma, CTCL），该病约占CTCL的30%。CD30+CLPD包括原发皮肤的间变大细胞淋巴瘤（Primary cutaneous anaplastic large cell lymphoma, p-cALCL）和淋巴瘤样丘疹病（Lymphomatiod papulosis, LyP）。LyP临床表现为慢性复发、可自愈的丘疹结节性疾病，该病可持续数月到几十年不等。大约有10%的患者进展为p-cALCL，10-20%p-cALCL患者生存率不到5年。CD30+CLPD皮肤活检的组织病理学特征主要表现为明显异型的CD30+T淋巴瘤细胞的出现，对于这些CD30+T淋巴瘤细胞的病理生物学特征知之甚少，尤其对CD30+CLPD发生发展机制仍然不清。特异的富含AT区结合蛋白（Special AT-rich region binding protein ，SATB1），一个特定的胸腺细胞染色质组织者，在大部分CD30+CLPD临床标本中高表达。SATB1通过独立于p53信号通路之外，直接抑制p21表达，使G1期细胞周期检测点失控，促进CD30+CLPD进展。在SATB1启动子内一个特定的CpG富集区随CD30+CLPD病情进展逐渐去甲基化，该区域去甲基化是导致SATB1表达上调的重要原因。本实验在p-cALCL细胞上揭示了一种新的调控细胞周期的信号通路，即SATB1↓→P21↑→细胞G1期阻滞，它为CD30+CLPD发病机制提供了新的见解，有助于新治疗方法产生。