BCL11A in normal B-cell biology and malignancy

描述（由申请人提供）：最近的几项观察结果突出了BCL11A在正常和恶性B细胞发育中的重要性。小鼠实验表明，BCL11A是一种锌指转录因子，对正常B细胞发育和生物体生存至关重要。BCL11A还与多种类型的B细胞恶性肿瘤有关，这是由于复发性染色体易位、基因扩增或逆转录病毒整合。尽管有这样的进展，BCL 11 A在正常B细胞分化过程中的功能，以及其蛋白质表达模式和下游靶基因的可能转录调控，在很大程度上是未知的。本研究计划通过（1）开发针对BCL 11A蛋白质亚型的新型抗体试剂、（2）利用cDNA微阵列技术鉴定和验证靶基因、（3）在胚胎干细胞中进行BCL 11A的条件基因靶向，进一步加深对这三个领域的理解。在目标（1）和（2）方面取得了重大进展。我们发现了一种新的BCL 11A亚型（结合目标（1）和（2）的成功），使我们能够检验BCL 11A是调节浆细胞分化的基因网络的组成部分的假设。此外，这种新的同种型可用于诊断源自后生殖中心B细胞的几种淋巴瘤，即霍奇金淋巴瘤、原发性渗出性淋巴瘤和多发性骨髓瘤所共有的共同转录谱。

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.