ONCOGENE DEREGULATION/TUMOR SUPPRESSOR GENE LOSS IN CLL

本项目的重点是B细胞和T细胞慢性淋巴细胞白血病的发病机制和发展的基因。它由四个相互关联和高度相互依存的项目和两个核心设施组成。项目1分别涉及BCL 2和TCL 1在B-CLL和T-CLL发病机制中的作用。我们拟探讨BCL 2在B-CLL中的上调机制和TCL 1在T-CLL中的作用机制。我们拟探讨BCL 2在B- CLL中的上调机制和TCL 1在T-CLL中的作用机制。我们还建议确定参与B-和T-CLL进展的其他基因的作用。第二个项目的重点是使用定位克隆方法克隆13q14.3的基因，该基因参与大多数人类B-CLLs的缺失。我们已经对超过750 Kb的关键染色体区域进行了测序，并正在测试B-CLL中突变和缺失的候选基因。第三个项目侧重于使用TcII敲除小鼠来评估TcII在淋巴发育中的作用。此外，本项目还提出研究白血病发生中TCL 1失调和ATM功能丧失的协同作用。第四个项目的重点是Tcll和Mtcpl及其突变体的三维表征，以及这两种癌蛋白与其他蛋白质的相互作用。两个核心设施，行政和蛋白质化学，为提案中描述的科学活动提供了出色的核心支持。

This program project focuses on the molecular mechanisms and the genes involved in the pathogenesis and progression of B- and T-cell chronic lymphocytic leukemia. It consists of four related and highly interdependent projects and two core facilities. Project 1 concerns the role of BCL2 and TCL1 in the pathogenesis of B-CLL and T-CLL respectively. We propose to investigate the mechanisms of up-regulation of BCL2 in B-CLL and the mechanisms of action of TCL1 in T-CLL. We propose to investigate the mechanisms of up-regulation of BCL2 in B- CLL and the mechanisms of action of TCL1 in T-CLL. We also propose to identify the role of other genes that are involved in the progression of B- and T-CLL. The second project focuses on the use of the positional cloning approach to clone a gene at 13q14.3 that is involved in deletions in most human B-CLLs. We have already sequenced over 750 Kb of the critical chromosomal region and are testing candidate genes for mutations and deletion in B-CLL The third project focuses on the use of Tcll knock out mice to assess the role of Tcll in lymphoid development. In addition this project proposes to investigate the cooperation of TCL1 deregulation and ATM loss of function in leukemogenesis. The fourth project focuses on the tridimensional characterization of Tcll and Mtcpl and their mutants and on the interaction of these two oncoproteins with other proteins. The two core facilities, administrative, and protein chemistry, provide outstanding core support for the scientific activities described in the proposal.