BCL11A in normal B-cell biology and malignancy

描述（由申请人提供）：BCL11A在正常和恶性b细胞发育中的重要性在最近的几项观察中得到强调。小鼠实验表明，BCL11A，一种锌指转录因子，对正常的b细胞发育和生物体的存活至关重要。由于复发性染色体易位、基因扩增或逆转录病毒整合，BCL11A也与多种类型的b细胞恶性肿瘤有关。尽管取得了这些进展，但BCL11A在正常b细胞分化过程中的功能、其蛋白表达模式以及可能对下游靶基因的转录调控在很大程度上仍是未知的。本项目拟通过(1)开发针对BCL11A蛋白亚型的新抗体试剂，(2)利用cDNA微阵列技术鉴定和验证靶基因，以及(3)胚胎干细胞中BCL11A的条件基因靶向，进一步加深我们对这三个领域的认识。在目标(1)和(2)方面取得了重大进展。我们发现了一种新的BCL11A亚型(加上Aims（1)和(2)的成功），使我们能够验证BCL11A是调节浆细胞分化的基因网络的一个组成部分的假设。此外，这种新的异构体可能用于诊断几种源于生发后中心B细胞的淋巴瘤共有的转录谱，即霍奇金淋巴瘤、原发性积液淋巴瘤和多发性骨髓瘤。

DESCRIPTION (provided by applicant): The emerging importance of BCL11A in normal and malignant B-cell development is highlighted by several recent observations. Experiments in the mouse have shown that BCL11A, a zinc-finger transcription factor, is essential for normal B-cell development as well as the survival of the organism. BCL11A also has been implicated in diverse types of B-cell malignancy due to recurrent chromosomal translocation, gene amplification, or retroviral integration. In spite of such progress, the functions of BCL11A during normal B-cell differentiation, as well as its protein expression pattern and its probable transcriptional regulation of downstream target genes, are largely unknown. This project proposes to further our understanding in these three areas by (1) the development of new antibody reagents directed against BCL11A protein isoforms, (2) the identification and validation of target genes using cDNA microarray technology, and (3) conditional gene-targeting of BCL11A in embryonic stem cells. Significant progress has been made in Aims (1) and (2). Our discovery of a novel BCL11A isoform (coupled with the success of Aims (1) and (2)) allows us to test the hypothesis that BCL11A is an integral component of a gene network regulating plasma cell differentiation. Furthermore, this novel isoform may be diagnostic for a common transcriptional profile shared by several lymphomas derived from post-germinal-center B cells, namely, Hodgkin lymphoma, primary effusion lymphoma, and multiple myeloma.