MLL translocations in t-AML

靶向DNA拓扑异构酶II的药物治疗后的治疗相关白血病经常涉及染色体11q23带上MLL基因的易位。这项研究将集中于MLL易位的功能分析，主要集中在MLL-CBP易位。MLL-CBP被克隆为t(11；16)(q23；p13)患者的MLL融合基因。除了一个例外，这些患者患有与治疗相关的白血病，相当大一部分患者表现为t-MDS。我们最近开发了用于MLL-CBP融合的体外和体内分析的小鼠模型系统。本项目涉及的研究包括进一步描述CBP对融合蛋白的关键功能，确定结构域交换对白血病和白血病前表型的功能影响，以及确定MLL-CBP融合对造血细胞谱系承诺和存活的影响。

Therapy-related leukemias following treatment with drugs that target DNA toposiomerase II frequently involve translocations of the MLL gene on chromosome band 11q23. This research project will focus on functional analysis of MLL translocations, with a major focus on the MLL-CBP translocation. MLL-CBP was cloned as the MLL fusion present in patients with a t(11;16) (q23;p13). With one exception, these patients had therapy-related leukemia, and a substantial proportion presented with t-MDS. We recently developed murine model systems for the in vitro and in vivo analysis of the MLL-CBP fusion. This project involves studies to further delineate critical functions contributed by CBP to the fusion protein, to determine the functional effects of domain swapping on leukemia and pre-leukemia phenotype, and to determine the effects of the MLL-CBP fusion on hematopoietic cell lineage commitment and survival.