Molecular Pathways to Thymic Lymphoma and Leukemia

描述（由申请人提供）：t细胞恶性肿瘤通常具有侵袭性和不可预测的行为，在儿童和成人中继续构成主要的临床管理问题。这一建议是基于一个中心假设，即提高对T淋巴细胞白血病和淋巴瘤（T- all /T- ll）中细胞增殖、分化和凋亡失调调控的分子途径的理解，最终将改善这些疾病的治疗。该计划项目资助（PPG）汇集了在调节正常胸腺细胞发育的分子途径方面具有专业知识的研究人员(dr。von Boehmer, Bassing and Alt)，胸腺细胞分裂的分子控制（Sicinski博士），早期T细胞存活的调节（Sicinski博士）。von Boehmer, AIt and Look)，调控发育的转录网络(dr。Young， Look和von Boehmer)，正常和异常TCR基因重排的控制(dr。basing和AIt)，人类t细胞白血病和淋巴瘤的分子发病机制（Look博士）和小鼠模型(dr。Bassing, AIt， Sicinski和von Boehmer)，生物统计学和生物信息学(dr。Neuberg和Liu)，以及基因表达和比较基因组杂交（CGH）阵列（Fox博士）。该研究将通过4个研究项目和3个核心的协调努力来完成。在项目1中，dr。Look和Young将在tal1介导的转录网络中识别下游靶基因，tal1介导的转录网络有助于人类t细胞恶性肿瘤中细胞增殖、分化和凋亡的无序调节。在项目2中，von Boehmer博士将研究发育转录控制网络异常与胸腺T-LL生成过程中tcr前信号传导之间的协同作用。在项目3中，Sicinski博士将确定TAL1和LYL1的过表达如何与T-ALL细胞的细胞周期机制相关联，特别是与关键的细胞周期调节蛋白D3和D2相关联。在项目4中，dr。Bassing和AIt将阐明导致与胸腺淋巴瘤相关的染色体易位的分子机制，重点是涉及ATM和H2AX的途径。这些项目将增加生物统计核心（Neuberg博士和Liu博士），以协助分析微阵列数据和优化动物实验设计；Molecular Core （Fox博士）执行基因表达和比较基因组杂交阵列；和行政核心（博士）。在人类T-LL和T-ALL的分子发病机制（Dr. Look, Project 1）、基因组定位分析（Dr. Young, Project 1）、t细胞发育（Dr. von Boehmer, Project 2）、细胞周期调节（Dr. Sicinski, Project 3）、染色体稳定性遗传调控（Dr. Sicinski, Project 3）等方面具有专业知识的项目研究者之间的研究互动的管理和协调。AIt和Bassing，项目4)，基因表达阵列(dr。Neuberg和Liu， Biostatistics Core，和Dr. Fox, Molecular Core)，以及识别共享结合基序的计算方法（Dr. Liu, Biostatistics Core）。这种相互作用有望加快这些项目和整个项目中产生重要发现的步伐。这个为期5年的项目的成功完成将提高对t细胞调控途径如何被破坏以启动和维持TALL和T-LL转化表型的理解，长期目标是确定抑制哪些基因可能导致开发针对这两种恶性疾病的新的高度特异性治疗策略。

DESCRIPTION (provided by applicant): The often aggressive and unpredictable behavior of T-cell malignancies continues to pose major clinical management problems in children and adults. This proposal is based on the central hypothesis that improved understanding of the molecular pathways that contributing to the disordered regulation of cell proliferation, differentiation, and apoptosis in T cell lymphoblastic leukemia and lymphoma (T-ALL/T-LL) will ultimately lead to improved therapy of these diseases. This Program Project Grant (PPG) brings together investigators with expertise in the molecular pathways regulating normal thymocyte development (Drs. von Boehmer, Bassing and Alt), the molecular control of thymocyte cell division (Dr. Sicinski), the regulation of early T cell survival (Drs. von Boehmer, AIt and Look), transcriptional networks regulating development (Drs. Young, Look and von Boehmer), the control of normal and aberrant TCR gene rearrangement (Drs. Bassing and AIt), the molecular pathogenesis of T-cell leukemia and lymphoma in humans (Dr. Look) and in murine models (Drs. Bassing, AIt, Sicinski, and von Boehmer), biostatistics and bioinformatics (Drs. Neuberg and Liu), and gene expression and comparative genomic hybridization (CGH) arrays (Dr. Fox). The research will be accomplished through the coordinated efforts of 4 research projects and 3 cores. In Project 1, Drs. Look and Young will identify downstream target genes within TAL1-mediated transcriptional networks that contribute to the disordered regulation of cell proliferation, differentiation, and apoptosis in human T-cell malignancies. In Project 2, Dr. von Boehmer will investigate the synergy between abnormalities in developmental transcriptional control networks and pre-TCR signaling in the generation of thymic T-LL. In Project 3, Dr. Sicinski will identify how overexpression of TAL1 and LYL1 is connected to the cell cycle machinery in T-ALL cells, specifically to the key cell cycle regulatory cyclins, D3 and D2. In Project 4, Drs. Bassing and AIt will elucidate the molecular mechanisms that lead to chromosomal translocations associated with thymic lymphomas, with focus on pathways involving ATM and H2AX. These projects will be augmented with a Biostatistics Core (Drs Neuberg and Liu), to assist with the analysis of microarray data and the optimal design of animal experiments; a Molecular Core (Dr. Fox) to perform gene expression and comparative genomic hybridization arrays; and an Administrative Core (Drs. Look and von Boehmer), to oversee the administration and coordination of the research interactions among program investigators with expertise in the molecular pathogenesis of human T-LL and T-ALL (Dr Look, Project 1), genome-scale location analysis (Dr. Young, Project 1), T-cell development (Dr. von Boehmer, Project 2), cell cycle regulation (Dr. Sicinski, Project 3), genetic regulation of chromosome stability (Drs. AIt and Bassing, Project 4), gene expression arrays (Drs. Neuberg and Liu, Biostatistics Core, and Dr. Fox, Molecular Core), and computational approaches to the identification of shared binding motifs (Dr. Liu, Biostatistics Core). Such interactions are expected to accelerate the pace at which important discoveries are generated in these projects and in the program as a whole. Successful completion of this 5-year program will improve understanding of how T-cell regulatory pathways are disrupted to initiate and maintain the transformed phenotype in TALL and T-LL, with the long-term goal to pinpoint genes whose inhibition could lead to the development of new and highly specific treatment strategies for these two malignant diseases.