Regulation of TAL1/SCL in T-Cell Leukemia

摘要： TAL1癌基因异常激活与高达60%的T细胞急性淋巴母细胞瘤相关 白血病(T-ALL)患者。它的异位表达也导致了小鼠白血病或淋巴瘤的发生。在……里面 相反，T-ALL细胞中TAL1的缺失失去了白血病表型，并诱导了细胞凋亡。此外， TAL1表达T-ALL亚型与预后差、复发率高有关。这些数据 提示TAL1癌基因异常在T-ALL的发生中起重要作用。但是，在 正常的造血功能，TAL1是基础螺旋-环-螺旋家族中的造血特异性成员 造血干细胞自我更新和急性淋巴细胞白血病发生发展所需的转录因子 造血血统。由于它与正常的造血分化和T细胞白血病有关，它 对于了解TAL1癌基因在正常造血细胞和急性T细胞白血病中的差异激活是至关重要的 白血病。理解调控TAL1转录调控的表观遗传机制将提供 对T-ALL疾病的表观遗传控制和发病机制的新见解 导致白血病诊断和治疗方法的新战略。 我们最近发现，TAL1的转录受到不同的染色体内和染色体间环的调控 正常的造血细胞和白血病细胞。这些染色体内和染色体间的环路改变了细胞- 键入与TAL1启动子相互作用的特定增强子。根据这些数据，我们假设 TAL1基因在T细胞特异转录活性位点附近的重新定位 在T-ALL中，核是异常激活TAL1癌基因所必需的。在这项建议中，我们将调查 连接染色质环与转录激活决定的潜在分子机制 TAL1癌基因以及阐明CTCF和增强子调控元件介导的染色质的作用 正常造血和白血病发生过程中TAL1基因调控的相互作用。具体目标 1)评估CTCF介导的基因组组织在调控增强子/启动子中的作用 造血和T细胞白血病过程中的相互作用和TAL1转录；2)分子研究 染色体间环导致T-ALL中TAL1癌基因异常激活的机制。

Abstract: Aberrant activation of TAL1 oncogene is associated with up to 60% of T-cell acute lymphoblastic leukemia (T-ALL) patients. Its ectopic expression also led to development of leukemia or lymphoma in mice. In contrast, deletion of TAL1 in T-ALL cells lost leukemic phenotype and induced apoptosis. Furthermore, the TAL1 expressing T-ALL subtype is associated with poor prognosis and high rate of relapse. These data suggest that dysregulation of TAL1 oncogene plays an important role in T-ALL leukemogenesis. However, in normal hematopoiesis, TAL1 is a hematopoietic-specific member of the basic helix-loop-helix family of transcription factors required for self-renewal of hematopoietic stem cells and the development of all hematopoietic lineages. Because of its relevance to normal hematopoietic differentiation and T-cell leukemia, it is critical to know how TAL1 oncogene is differentially activated in normal hematopoietic cells and T-cell acute leukemia. Understanding of the epigenetic mechanisms governing TAL1 transcriptional regulation will provide a new insight into epigenetic control of hematopoiesis as well as pathogenesis of T-ALL diseases which may lead to new strategies for leukemia diagnosis and therapeutic approaches. We recently found that TAL1 transcription is regulated by different intra- and interchromosomal loops in normal hematopoietic and leukemia cells, respectively. These intra- and interchromosomal loops alter the cell- type specific enhancers that interact with the TAL1 promoter. Based on these data, we hypothesize that repositioning of the TAL1 gene in a close proximity with T-cell specific transcriptionally active loci within nucleus is essential for aberrantly activating TAL1 oncogene in T-ALL. In this proposal, we will investigate the underlying molecular mechanisms that connect chromatin loops with transcriptional activation decision of the TAL1 oncogene as well as elucidate the role of CTCF and enhancer regulatory elements mediated chromatin interactions in regulation of TAL1 gene during normal hematopoiesis and leukemogenesis. The specific aims are: 1) Evaluate the role of CTCF mediated genome organization in regulation of enhancer/ promoter interaction and TAL1 transcription during hematopoiesis and T cell leukemogenesis; 2) Study the molecular mechanisms by which interchromosomal loops result in aberrant activation of TAL1 oncogene in T-ALL.