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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：
8459574
负责人：
CARLO M CROCE
金额：
$ 87.77万
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 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459574
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 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 screening

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）：ALL1 相关白血病占婴儿和治疗相关白血病的大多数。 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方面发挥着关键作用。 C. Croce 和 E. Canaani 是 ALL1 的共同发现者，A. Mazo 是 TRX 的发现者。我们的目标是进一步了解 ALL1 融合蛋白如何引发白血病。由于 ALL1 和 TRX 在结构和功能上具有很强的同源性，对 TRX 的研究产生了意想不到的重要见解，不仅与 TRX 有关，也与 ALL1 相关。我们最近取得的主要成就包括：1) ALL1 融合蛋白与 microRNA 加工酶 Drosha 一起与 miR-191 结合，上调其表达，2) ALL1 相关白血病细胞系中 MEIS1 和 HOX A10 或 A9 的敲低会损害其致白血病性，3) TRX 在转录延伸和延伸因子招募中不可或缺的作用，4) 发挥作用 ubx 基因上游非编码序列的 TRX 依赖性转录抑制 ubx 编码区的表达，5) 与 ALL1 融合的正常伴侣蛋白共同招募后者的靶标，6) TRX 和 ALL1 在表观遗传中的潜在作用。在我们的研究中，我们使用高度复杂和多样化的方法，包括全基因组定位分析、全基因组表达谱、多蛋白复合物的纯化及其组分的质谱表征、体外和体内分析microRNA的加工、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、分析归巢、迁移和植入受操纵的白血病细胞，将表达 TRX 靶标的果蝇胚胎核与不表达 TRX 靶标的核分开等。我们坚信，对 ALL1/TRX 和 ALL1 白血病发生问题的如此广泛的研究将为基因融合介导的白血病发生和基因调控的基础提供更深入的理解和新的视野。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

cMyc/miR-125b-5p signalling determines sensitivity to bortezomib in preclinical model of cutaneous T-cell lymphomas.

DOI：
10.1371/journal.pone.0059390
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Manfè V;Biskup E;Willumsgaard A;Skov AG;Palmieri D;Gasparini P;Laganá A;Woetmann A;Ødum N;Croce CM;Gniadecki R
通讯作者：
Gniadecki R

miR-221/222 overexpession in human glioblastoma increases invasiveness by targeting the protein phosphate PTPμ.

DOI：
10.1038/onc.2011.280
发表时间：
2012-02-16
期刊：
ONCOGENE
影响因子：
8
作者：
Quintavalle, C.;Garofalo, M.;Zanca, C.;Romano, G.;Iaboni, M.;De Caro, M. del Basso;Martinez-Montero, J. C.;Incoronato, M.;Nuovo, G.;Croce, C. M.;Condorelli, G.
通讯作者：
Condorelli, G.

MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review.

DOI：
10.1002/emmm.201100209
发表时间：
2012-03
期刊：
EMBO MOLECULAR MEDICINE
影响因子：
11.1
作者：
Iorio, Marilena V.;Croce, Carlo M.
通讯作者：
Croce, Carlo M.

miR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR-221 and 222.

DOI：
10.1038/onc.2011.260
发表时间：
2012-02-02
期刊：
ONCOGENE
影响因子：
8
作者：
Acunzo, M.;Visone, R.;Romano, G.;Veronese, A.;Lovat, F.;Palmieri, D.;Bottoni, A.;Garofalo, M.;Gasparini, P.;Condorelli, G.;Chiariello, M.;Croce, C. M.
通讯作者：
Croce, C. M.

miR221/222 in cancer: their role in tumor progression and response to therapy.