混合系列急性白血病分子遗传学特征及MEF2C基因致白血病机制研究

The majority of patients with acute leukemia can be unequivocally assigned to a specific lineage origin of myeloid, B-lymphoid, or T-lymphoid. However, the lineage is difficult to define in about 2-5% of patients with acute leukemia even after they received comprehensive morphologic and immunophenotypic analysis. The 2008 WHO classification of tumors of hematopoietic and lymphoid tissues introduced a new designation for this disease, now termed mixed-phenotype acute leukemia (MPAL). However, given the dearth of reports hitherto, the clinical and molecular genetic features of MPAL remain largely unknown. In this study, we identified a cohort of patients with MPAL by screening about 4,800 patients with acute leukemia. Moreover, we established the first MPAL cell line, JIH-5, from a female patient with MPAL. Distinct clinical, cytogenetic, and molecular genetic features were showed in MPAL patients when compared with patients with acute myeloid leukemia or acute lymphoblastic leukemia. We also identified a novel genetic microdeletion involving an important transcription factor, MEF2C, in 16.7% of patients with MPAL. We plan to determine the clinical and laborotary characteristics, cytogentic and molecular genetic features, and pathogenesis of MPAL using multiple in vivo and in vitro techniques, such as gene expression microarray, array-based comparative genomic hybridization, gene transfection, RNA interference, and animal models. The role of MEF2C in leukemogenesis of MPAL will be determined. This study will provide more details on the pathogenesis of MPAL.

混合系列急性白血病(MPAL)是一类按照细胞形态、免疫表型难以诊断为髓性或淋巴细胞性急性白血病的疾病，WHO（2008）分型将其定义为独立的白血病类型。目前，有关 MPAL的研究极少，临床和生物学特征尚不明确，尤其缺少分子遗传学的研究。本课题组自4800余例急性白血病患者中，筛选到国际最大一组MPAL病例，并从中成功建立了国际第一株MPAL细胞系JIH-5,发现该类患者具有独特的临床、细胞遗传学和分子遗传学特征，并在16.7%的患者中首次发现存在转录因子MEF2C的基因组微缺失。本课题拟以JIH-5细胞系和该组患者为研究对象，采用全外显子测序、array-CGH、基因转染、RNA干扰和模式动物等手段,从体内外两方面揭示MPAL的临床和实验室特征、细胞和分子遗传学异常及发病机制，并重点阐述MEF2C基因参与MPAL发病的机制。本课题将为阐明MPAL的发病机制、寻找新的治疗靶点理论和实验依据。

混合系列急性白血病(MPAL)是一类按照细胞形态、免疫表型难以诊断为髓性或淋巴细胞性急性白血病的疾病，WHO（2008）分型将其定义为独立的白血病类型。目前，有关MPAL的研究极少，临床和生物学特征尚不明确，尤其缺少分子遗传学的研究。本课题拟依据前期的研究成果，以国际最大的一组MPAL患者为研究对象，采用全基因组测序、array-CGH芯片、基因表达谱芯片、RQ-PCR、基因转染等手段，阐述MPAL的临床特点、实验室特征、细胞遗传学异常、分子遗传学特征以及发病机制，并重点阐述MEF2C基因参与MPAL发病的机制。结果表明成人MPAL是一组异质性较大的疾病，在急性白血病中发生率为2.4%。MPAL以B淋系和髓系混合表达最为常见，64.1%的患者存在细胞遗传学异常，其中以复杂核型和Ph染色体异常相对常见。现有化疗方案预后差，异基因造血干细胞移植有可能改善其长期生存。多重巢式 PCR 技术可以提高MPAL患者基因重排的检出率。MPAL患者中存在高频率的基因变异率，75%的成人MPAL患者在初诊时可以被检出存在基因变异，包括表观遗传学相关基因（42.9%）和重要转录因子的相关基因（32.1%）。在 2 例MPAL患者中首次发现存在再现性的转录因子MEF2C的新激活方式-基因缺失。AML患者中MEF2C基因mRNA表达水平明显升高，对于正常核型AML患者而言，荧光实时定量检测MEF2C基因mRNA 表达水平有提示预后的价值；沉默MEF2C基因表达能抑制AML细胞株Dami 的增殖。此外，我们建立了国际上第一株B淋系和髓系共表达的混合表型急性白血病细胞系JIH-5，并对其进行了较为完整的生物学鉴定。本课题将为阐明MPAL的克隆起源、阐述其发病机制、寻找新的治疗靶点、实现个体化治疗提供理论和实验依据。

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