Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia

11q23 染色体异常在急性白血病病因中的作用

• 批准号: 7561829
• 负责人: CARLO M CROCE
• 金额: $ 101.14万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-05 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561829
• 关键词: Role; 11q23; Chromosome; Abnormalities; Causation

DESCRIPTION (provided by applicant): ALL1-associated leukemias account for the majority of infant and therapy-related leukemias. ALL1 is the human homologue of Drosophila TRITHORAX (TRX) which has a critical role in setting up the body pattern during embryonic development. C. Croce and E. Canaani are the co-discoverers of ALL1, and A. Mazo is the discoverer of TRX. Our goal is to further understand how ALL1 fusion proteins trigger leukemia. Because of the strong homology in structure and function between ALL1 and TRX, investigations of TRX have yielded unexpected important insights pertinent not only for TRX, but for ALL1 as well. Major achievements we made recently include: 1) ALL1 fusion proteins bind together with the microRNAs processor enzyme Drosha to miR-191 to upregulate its expression, 2) knockdown of MEIS1 and HOX A10 or A9 in an ALL1-associated leukemic cell line impairs its leukemogenicity, 3) indispensable role of TRX in transcriptional elongation and in recruitment of elongation factors, 4) a role of TRX-dependent transcription of non-coding sequences upstream to the ubx genes in inhibiting expression of ubx coding region, 5) co-recruitment of normal partner proteins with ALL1 fusions to targets of the latter, 6) potential role for TRX and ALL1 in Epigenetic inheritance. In our studies we use highly sophisticated and varied methodologies, including genome-wide location analysis, genome-wide expression profiling, purification of multiprotein complexes and characterization of their components by mass spectroscopy, assaying microRNAs processing in vitro and in vivo, applying array screening to examine expression of microRNAs, lentiviral-based transduction of shRNAs into hematopoietic cells, assaying homing, migration and engraftment of manipulated leukemic cells, separating Drosophila embryo nuclei that express a TRX target from those nuclei that do not, etc. We strongly believe that such a wide-angle attack on the issues of ALL1/TRX and ALL1 leukemogenesis will provide deeper understanding and new vision of the fundamentals of gene fusion-mediated leukemogenesis and of gene regulation.

描述（由申请人提供）：ALL 1相关白血病占婴儿和治疗相关白血病的大多数。ALL 1是果蝇TRITHORAX（TRX）的人类同源物，TRX在胚胎发育期间建立身体模式中具有关键作用。C. Croce和E. Canaani和A.马佐是TRX的发现者。我们的目标是进一步了解ALL 1融合蛋白如何引发白血病。由于ALL 1和TRX之间在结构和功能上的高度同源性，对TRX的研究已经产生了意想不到的重要见解，不仅与TRX有关，而且与ALL 1也有关。我们最近取得的主要成就包括：1）ALL 1融合蛋白与microRNA处理器酶Drosha一起结合到miR-191以上调其表达，2）在ALL 1相关白血病细胞系中敲低MEIS 1和HOX A10或A9损害其致白血病性，3）TRX在转录延伸和延伸因子募集中不可或缺的作用，4）Ubx基因上游非编码序列的TRX依赖性转录在抑制Ubx编码区表达中的作用，5）正常配偶体蛋白与ALL 1融合体共募集至后者的靶点，6）TRX和ALL 1在表观遗传中的潜在作用。 在我们的研究中，我们使用了高度复杂和多样的方法，包括全基因组定位分析，全基因组表达谱分析，多蛋白复合物的纯化和质谱分析其组分，体外和体内测定microRNA加工，应用阵列筛选来检查microRNA的表达，基于慢病毒的shRNA转导到造血细胞中，测定归巢，操作的白血病细胞的迁移和植入，将表达TRX靶标的果蝇胚胎细胞核与不表达TRX靶标的那些细胞核分离等。 我们坚信，这样一个广角攻击的ALL 1/TRX和ALL 1 leukemogenesis的问题，将提供更深入的理解和新的视野的基因融合介导的leukemogenesis和基因调控的基础。