Regulation of TAL1/SCL in T-Cell Leukemia

T 细胞白血病中 TAL1/SCL 的调控

• 批准号: 10094201
• 负责人: Suming Huang
• 金额: $ 31.51万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094201
• 关键词: Acute T Cell Leukemia; Acute leukemia; Apoptosis; Binding Sites; Biological Assay; CRISPR/Cas technology; Cell Nucleus; Cells; Chromatin; Chromatin Loop; Chromosomal translocation; Chromosome 16; DNA; DNA Binding Domain; Data; Development; Diagnosis; Disease; Ectopic Expression; Enhancers; Epigenetic Process; Erythroid Cells; Family; Gene Expression Regulation; Genetic Transcription; Genome; Helix-Turn-Helix Motifs; Hematopoiesis; Hematopoietic; Human; Lead; Leukemic Cell; Link; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular; Mus; Oncogenes; Oncogenic; Pathogenesis; Patients; Phenotype; Play; Process; Prognosis; RNA; Regulation; Regulatory Element; Relapse; Role; Stem Cell Development; Structure; T-Cell Leukemia; T-Lymphocyte; TAL1 gene; Testing; Therapeutic; Transcriptional Activation; Transcriptional Regulation; Xenograft Model; Zinc Fingers; acute T-cell lymphoblastic leukemia cell; base; cell type; chromosome conformation capture; gain of function mutation; genome editing; hematopoietic differentiation; hematopoietic stem cell self-renewal; human model; insight; leukemia; leukemogenesis; loss of function; member; novel; promoter; success; targeted treatment; transcription factor

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.

摘要： TAL 1癌基因的异常激活与高达60%的T细胞急性淋巴细胞白血病相关。 白血病（T-ALL）患者。它的异位表达也导致小鼠白血病或淋巴瘤的发展。在 相反，T-ALL细胞中TAL 1的缺失丧失了白血病表型并诱导凋亡。而且 表达TAL 1的T-ALL亚型预后差，复发率高。这些数据 提示TAL 1癌基因调控异常在T-ALL白血病发生中起重要作用。但在 正常造血，TAL 1是造血特异性的基本螺旋-环-螺旋家族成员， 造血干细胞自我更新和所有造血干细胞发育所需的转录因子 造血谱系由于其与正常造血分化和T细胞白血病相关， 了解TAL 1癌基因在正常造血细胞和T细胞急性白血病细胞中的差异激活是至关重要的。 白血病对TAL 1转录调控的表观遗传机制的理解将提供 对造血的表观遗传控制以及T-ALL疾病的发病机制有了新的认识， 从而为白血病诊断和治疗方法带来新的策略。 我们最近发现，TAL 1的转录受不同的染色体内和染色体间环的调控， 正常造血细胞和白血病细胞。这些染色体内和染色体间的环改变了细胞- 与TAL 1启动子相互作用的类型特异性增强子。根据这些数据，我们假设， 将TAL 1基因重新定位在T细胞特异性转录活性位点附近， 细胞核是T-ALL异常激活TAL 1癌基因的关键。在本提案中，我们将调查 潜在的分子机制，连接染色质环与转录激活的决定， TAL 1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TAL 1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增强子/启动子调控中的作用， 2）研究TAL 1基因在造血和T细胞白血病发生中的分子作用， 染色体间环导致T-ALL中TAL 1癌基因异常激活的机制。

项目成果

Paraspeckle Protein NONO Promotes TAZ Phase Separation in the Nucleus to Drive the Oncogenic Transcriptional Program.

• DOI: 10.1002/advs.202102653
• 发表时间: 2021-12
• 期刊: Advanced science (Weinheim, Baden-Wurttemberg, Germany)
• 作者: Wei Y;Luo H;Yee PP;Zhang L;Liu Z;Zheng H;Zhang L;Anderson B;Tang M;Huang S;Li W
• 通讯作者: Li W