Molecular Pathways to Thymic Lymphoma and Leukemia

胸腺淋巴瘤和白血病的分子途径

• 批准号: 7250866
• 负责人: A. THOMAS LOOK
• 金额: $ 195.83万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-11 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7250866
• 关键词: Molecular; Pathways; Thymic; Lymphoma; Leukemia

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.

描述(由申请人提供)：T细胞恶性肿瘤的侵袭性和不可预见性的行为继续给儿童和成人带来主要的临床管理问题。这一建议基于一个中心假设，即对T细胞淋巴母细胞白血病和淋巴瘤(T-ALL/T-LL)中导致细胞增殖、分化和凋亡调控紊乱的分子途径的进一步了解将最终导致这些疾病的治疗水平的提高。该计划项目赠款(PPG)汇集了以下领域的研究人员：调节正常胸腺细胞发育的分子途径(冯·伯默博士、巴辛博士和阿尔特博士)、胸腺细胞分裂的分子控制(西辛斯基博士)、早期T细胞存活的调控(冯·伯默博士、Ait和Look博士)、转录网络调控发育(杨博士、Look和von Boehmer博士)、正常和异常TCR基因重排的控制(Bassing和Ait博士)、人类T细胞白血病和淋巴瘤的分子发病机制(Dr.Look)以及小鼠模型(Drs.Bassing、Ait、Sininski和von Boehmer)，以及生物统计学和生物信息学(Neuberg和Liu博士)以及基因表达和比较基因组杂交(CGH)阵列(Fox博士)。这项研究将通过4个研究项目和3个核心的协调努力完成。在项目1中，Look和Young博士将确定TAL1介导的转录网络中的下游目标基因，这些基因有助于人类T细胞恶性肿瘤中细胞增殖、分化和凋亡的无序调控。在项目2中，von Boehmer博士将研究发育转录控制网络异常和TCR前信号在胸腺T-LL生成中的协同作用。在项目3中，西辛斯基博士将确定TAL1和LYL1的过度表达如何与T-ALL细胞的细胞周期机制有关，特别是与关键的细胞周期调节周期蛋白D3和D2有关。在项目4中，巴辛博士和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。这些项目将增加一个生物统计核心(DRS Neuberg和Liu)，以协助分析微阵列数据和优化动物实验设计；一个分子核心(Dr.Fox)，执行基因表达和比较基因组杂交阵列；和一个行政核心(博士Look和von Boehmer)，以监督项目调查人员之间研究互动的管理和协调，这些研究人员具有以下方面的专业知识：人类T-LL和T-ALL的分子发病机制(Dr Look，项目1)、基因组规模位置分析(Young博士，项目1)、T细胞发育(冯·Boehmer博士，项目2)、细胞周期调节(博士Sininski，项目3)、染色体稳定性的遗传调节(博士Ait和Bating，项目4)、基因表达阵列(Neuberg和Liu博士，生物统计学核心，以及Fox博士，分子核心)，和识别共享结合基序的计算方法(刘博士，生物统计学核心)。这种互动预计将加快在这些项目和整个计划中产生重要发现的速度。这项为期5年的计划的成功完成将提高对T细胞调节通路如何被扰乱以启动和维持TALL和T-LL转化表型的理解，长期目标是准确定位其抑制可能导致开发针对这两种恶性疾病的高度特异性的新的治疗策略的基因。