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Studies of the t(2;13) of alveolar rhabdomyosarcoma

腺泡状横纹肌肉瘤t(2;13)的研究

基本信息

批准号：
7257048
负责人：
FREDERIC G BARR
金额：
$ 33.81万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-08-30 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7257048
关键词：
12q13 2p24 Affinity Alternative Splicing Alveolar Rhabdomyosarcoma Attenuated Behavior Binding Binding Sites Biological Assay Boxing CDK4 gene Candidate Disease Gene Cell Culture System Cell Line Cells Chimeric Proteins Chromosomal translocation Condition Conflict (Psychology)Cultured Cells DNA Binding DNA Binding Domain Dominant-Negative Mutation Dose End Point Equilibrium Estrogen Receptors Evaluation Event Exertion FOXO1A gene Fibroblasts Gene Amplification Gene Expression Gene Fusion Gene Transfer Genes Genetic Growth In Vitro Ligand Binding Domain MDM2 gene MDM2 gene MYCN gene Malignant Childhood Neoplasm Mediating Methodology Modification Mus Mutate Mutation Myoblasts NIH 3T3 Cells Numbers Oncogenes Oncogenic Other Finding Other Genetics PAX3 gene PAX7 gene Pathway interactions Process Protein Isoforms Protein Overexpression Proteins Range Resistance Role Striated Muscles System TP53 gene Tamoxifen Transcription Coactivator United States National Institutes of Health base fusion gene immortalized cell mutant resistance mechanism response retroviral transduction role model transcription factor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer of the striated muscle lineage that is characterized by 2;13 or 1;13 chromosomal translocations. These events juxtapose PAX3 or PAX7 with FKHR to create fusion genes encoding PAX3-FKHR or PAX7-FKHR fusion products. The wild-type genes encode transcription factors, and the fusion products combine the PAX3 or PAX7 DNA binding domain and FKHR activation domain to create potent transcriptional activators. Though some initial studies indicated that these fusion proteins induce oncogenic effects, more recent studies have revealed genetic and phenotypic complexities that require refinement of the model for the role of these fusion products in ARMS tumorigenesis. These complexities are evidenced by gene transfer studies of these fusion genes that show oncogenic behavior in some conditions and growth suppressive behavior in other conditions. In addition, there are frequent alternative splicing events in the PAX3/PAX7-FKHR DNA binding domain that generate a mixture of functionally distinct isoforms. Finally, there are secondary genetic changes in ARMS cells, including gene amplification and small mutations, which may interact with the translocation events. To explain these findings, the hypothesis is proposed that the growth effects of these fusion proteins are initially dependent on the level of transcriptional activity, with oncogenic effects predominating at lower activity and growth suppression predominating at higher activity. The final balance between these growth effects as well as additional phenotypic activities is postulated to be modulated by other factors, including the mixture of functionally distinct isoforms and secondary genetic changes. The current proposal will focus on the PAX3-FKHR fusion protein and will explore these hypotheses by using inducible cell culture systems that display this range of growth effects to analyze the functional requirements and gene expression events associated with oncogenic effects and growth suppression. Cell culture and in vitro systems will be used to assess differences in DNA binding activity, phenotypic effects, and downstream expression events between the two PAX3-FKHR isoforms. Finally, these studies will investigate the role of amplified oncogenes and other genetic events in modifying the function and downstream effects of the fusion protein. These combined studies will permit a comprehensive evaluation of the relationship between PAX3-FKHR transcriptional function, target gene expression, phenotypic effects, and collaborating events, and will thereby better define the role of these fusion genes in ARMS tumorigenesis.

描述（由申请人提供）：腺泡状横纹肌肉瘤（ARMS）是一种侵袭性的横纹肌谱系儿科癌症，其特征为2;13或1;13染色体易位。这些事件将PAX 3或PAX 7与FKHR并置以产生编码PAX 3-FKHR或PAX 7-FKHR融合产物的融合基因。野生型基因编码转录因子，融合产物联合收割机结合PAX 3或PAX 7 DNA结合结构域和FKHR激活结构域以产生有效的转录激活因子。虽然一些初步的研究表明，这些融合蛋白诱导致癌作用，最近的研究揭示了遗传和表型的复杂性，需要完善的模型，这些融合产物在ARMS肿瘤发生的作用。这些融合基因的基因转移研究证明了这些复杂性，这些融合基因在某些条件下表现出致癌行为，在其他条件下表现出生长抑制行为。此外，在PAX 3/PAX 7-FKHR DNA结合结构域中存在频繁的选择性剪接事件，其产生功能不同同种型的混合物。最后，ARMS细胞中存在继发性遗传变化，包括基因扩增和小突变，这些变化可能与易位事件相互作用。为了解释这些发现，提出的假设是，这些融合蛋白的生长效果最初依赖于转录活性的水平，在较低的活性和生长抑制占主导地位的高活性的致癌作用占主导地位。这些生长效应以及额外的表型活性之间的最终平衡被假定为由其他因素调节，包括功能不同的同种型和次级遗传变化的混合物。目前的建议将集中在PAX 3-FKHR融合蛋白，并将探索这些假设，通过使用诱导型细胞培养系统，显示这一范围的生长效应，分析功能要求和基因表达事件与致癌作用和生长抑制。将使用细胞培养和体外系统评估两种PAX 3-FKHR亚型之间DNA结合活性、表型效应和下游表达事件的差异。最后，这些研究将探讨扩增的癌基因和其他遗传事件在修饰融合蛋白的功能和下游效应中的作用。这些联合研究将允许PAX 3-FKHR转录功能，靶基因表达，表型效应和协作事件之间的关系进行全面评估，从而更好地确定这些融合基因在ARMS肿瘤发生中的作用。

项目成果

期刊论文数量（43）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of expression of stromal-derived factor-1 receptors: CXCR4 and CXCR7 in human rhabdomyosarcomas.

DOI：
10.1158/1541-7786.mcr-09-0259
发表时间：
2010-01
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
Tarnowski M;Grymula K;Reca R;Jankowski K;Maksym R;Tarnowska J;Przybylski G;Barr FG;Kucia M;Ratajczak MZ
通讯作者：
Ratajczak MZ

Molecular diagnosis of ewing family tumors: too many fusions... ?

尤文家族肿瘤的分子诊断：融合过多......？

DOI：
10.2353/jmoldx.2007.070080
发表时间：
2007
期刊：
The Journal of molecular diagnostics : JMD
影响因子：
0
作者：
Barr,FredericG;Womer,RichardB
通讯作者：
Womer,RichardB

Overlapping and distinct role of CXCR7-SDF-1/ITAC and CXCR4-SDF-1 axes in regulating metastatic behavior of human rhabdomyosarcomas.

DOI：
10.1002/ijc.25245
发表时间：
2010-12-01
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Grymula, Katarzyna;Tarnowski, Maciej;Wysoczynski, Marcin;Drukala, Justyna;Barr, Frederic G.;Ratajczak, Janina;Kucia, Magdalena;Ratajczak, Mariusz Z.
通讯作者：
Ratajczak, Mariusz Z.

Genetics and the biologic basis of sarcomas.

肉瘤的遗传学和生物学基础。