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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(申请人提供)：ALL1相关性白血病占婴儿白血病和治疗相关白血病的大部分。ALL1是果蝇Trithorax(Trx)的人类同源物，在胚胎发育过程中对建立身体模式具有关键作用。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融合蛋白如何触发白血病。由于AlL1和Trx在结构和功能上有很强的同源性，对Trx的研究不仅对Trx，而且对AlL1都产生了意想不到的重要见解。我们最近取得的主要成就包括：1)ALL1融合蛋白与microRNAs处理器酶DROSHA结合到miR-191上调其表达；2)在ALL1相关的白血病细胞系中，Meis1和Hox A10或A9的敲除削弱了其致白血病活性；3)Trx在转录延长和延长因子募集中发挥了不可或缺的作用；4)Ubx基因上游非编码序列的Trx依赖转录抑制了Ubx编码区的表达；5)正常伴侣蛋白与ALL1融合共同招募到后者的靶点；6)Trx和ALL1在表观遗传中的潜在作用。在我们的研究中，我们使用了高度复杂和多样化的方法，包括全基因组定位分析，全基因组表达谱分析，多蛋白复合体的纯化及其组成的质谱学表征，分析在体外和体内的microRNAs加工，应用阵列筛选来检测microRNAs的表达，基于慢病毒的shRNA转导到造血细胞，分析操纵的白血病细胞的归巢、迁移和植入，分离表达TRX靶点的果蝇胚胎核和不表达TRX靶点的核，等等。我们坚信，对ALL1/TRX和ALL1白血病发生问题的这种广角攻击将提供对基因融合介导的白血病发生和基因调控的基础的更深层次的理解和新的视野。

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.