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通过最近的几项观察得到了强调。在小鼠身上的实验表明，BCL11A是一种锌指转录因子，对B细胞的正常发育以及生物体的生存都是必不可少的。由于反复的染色体易位、基因扩增或逆转录病毒整合，BCL11A还与多种类型的B细胞恶性肿瘤有关。尽管有这些进展，但BCL11A在正常B细胞分化过程中的功能，以及它的蛋白表达模式和对下游靶基因可能的转录调控，在很大程度上是未知的。本项目建议通过(1)针对BCL11A蛋白亚型的新型抗体试剂的开发，(2)利用基因芯片技术鉴定和验证靶基因，以及(3)在胚胎干细胞中进行BCL11A的条件性基因打靶，从而加深我们在这三个领域的理解。AIMS(1)和(2)已取得重大进展。我们发现了一种新的BCL11A亚型(再加上AIMS(1)和(2)的成功)，这使得我们能够检验BCL11A是调控浆细胞分化的基因网络的组成部分的假设。此外，这种新的异构体可能对几种来源于生发中心后B细胞的淋巴瘤共同的转录特征进行诊断，即霍奇金淋巴瘤、原发渗出性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.