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

基本信息

批准号：
8259219
负责人：
CARLO M CROCE
金额：
$ 93.73万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-05 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8259219
关键词：
11q23 ASCL1 gene Accounting Achievement Acute leukemia American Biological Assay Body Patterning Cell Line Cell Nucleus Cells Child Chimeric Proteins Chromosome abnormality Code Comprehension DNA Sequence Rearrangement Development Disease Drosophila genus Elongation Factor Embryo Embryonic Development Engraftment Enzymes Epigenetic Process Etiology Event Failure Functional RNA Gene Expression Gene Expression Regulation Gene Fusion Gene Targeting Genes Genetic Transcription Goals Hematopoietic Histones Homing Homologous Gene Human In Vitro Infant Investigation Lead Leukemic Cell Location MEIS1 gene MLL gene Mass Spectrum Analysis Mediating Methodology MicroRNAs Molecular Molecular Profiling Multiprotein Complexes Pathogenesis Pathway interactions Patients Platelet Factor 4 Play Polycomb Positioning Attribute Process Protein Binding Proteins Regulation Risk Role Screening procedure Structure Transplantation Up-Regulation Vision adult leukemia base chemotherapy genome-wide genome-wide analysis histone modification improved in vivo innovation insight leukemia leukemogenesis migration novel therapeutics outcome forecast overexpression research study

项目摘要

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）：所有与1个相关的白血病解释了大多数婴儿和治疗相关的白血病。 All1是果蝇Trithorax（TRX）的人类同源物，它在胚胎发育过程中建立身体模式中具有关键作用。 C. Croce和E. Canaani是All1的共同发现，A。Mazo是TRX的发现者。我们的目标是进一步了解All1融合蛋白如何触发白血病。由于ALL1和TRX之间的结构和功能具有很强的同源性，TRX的研究产生了意外的重要见解，不仅与TRX有关，而且对All1也产生了相关的。我们最近取得的主要成就包括：1）All1融合蛋白与MiroRNAS处理器酶Drosha与MiR-191结合在一起，以上调其表达，2）MEIS1和HOX A10或HOX A10或A9在ALL1相关的白血病系中的able型和HOX A10或A9的表达，3）在其白血上的作用，3）不兼具的效果，3）TRONS的富有作用； UBX基因上游的非编码序列在抑制UBX编码区的表达中的非编码序列的转录的转录，5）正常伴侣蛋白与后者靶标的所有融合，6）在表观遗传中的TRX和All1的潜在作用。在我们的研究中，我们使用高度复杂和多样化的方法学，包括全基因组的位置分析，全基因组的表达分析，多蛋白质复合物的纯化以及通过质谱法对其成分进行表征，分析体外和体内microRNAS处理，将阵营筛选到透明膜的迁移中，将其筛选为基于透明膜的迁移，并将其迁移到基于透明度的转化，并将其转化为shrotinition shrociention shrocition shrotinition shrocition shroction shroction shroction shrotinity shroction shrotinity shroction shrotinity shrotinity shrotinity shrotinity，植入操纵的白血病细胞，将果蝇胚胎核分开，该核核与那些没有的核表达trx靶的核核，等等。我们坚信，对All1/TRX和All1白血病发生的问题如此广泛的攻击将为基因融合介导的白血病和基因调节提供更深入的理解和新的视野。