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.

抽象的： TAL1 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。它的异位表达还导致小鼠患上白血病或淋巴瘤。在 相比之下，T-ALL 细胞中 TAL1 的缺失会丧失白血病表型并诱导细胞凋亡。此外， 表达 TAL1 的 T-ALL 亚型与不良预后和高复发率相关。这些数据 表明 TAL1 癌基因的失调在 T-ALL 白血病发生中起重要作用。然而，在 正常造血功能，TAL1 是基本螺旋-环-螺旋家族的造血特异性成员 造血干细胞自我更新和所有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，因此 了解 TAL1 癌基因在正常造血细胞和 T 细胞急性细胞中如何差异激活至关重要 白血病。了解控制 TAL1 转录调控的表观遗传机制将提供 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，这可能 导致白血病诊断和治疗方法的新策略。 我们最近发现TAL1转录受到不同染色体内和染色体间环的调节 分别为正常造血细胞和白血病细胞。这些染色体内和染色体间环改变了细胞 与 TAL1 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 TAL1 基因重新定位，使其与 T 细胞特异性转录活性位点非常接近 细胞核对于 T-ALL 中 TAL1 癌基因的异常激活至关重要。在本提案中，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 是： 1) 评估 CTCF 介导的基因组组织在增强子/启动子调节中的作用 造血和 T 细胞白血病发生过程中的相互作用和 TAL1 转录； 2）研究分子 T-ALL 中染色体间环导致 TAL1 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.

Paraspeckle 蛋白 NONO 促进细胞核中的 TAZ 相分离，从而驱动致癌转录程序。

• 发表时间: 2021
• 作者: Wei, Yiju;Luo, Huacheng;Yee, Patricia P;Zhang, Lijun;Liu, Zhijun;Zheng, Haiyan;Zhang, Lei;Anderson, Benjamin;Tang, Miaolu;Huang, Suming;Li, Wei
• 通讯作者: Li, Wei

Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia.

人类 AML 的功能重建揭示了干细胞起源和难治性 MLL 重排白血病的脆弱性。

• 发表时间: 2021
• 影响因子: 17.1
• 作者: Zeisig, Bernd B;Fung, Tsz Kan;Zarowiecki, Magdalena;Tsai, Chiou Tsun;Luo, Huacheng;Stanojevic, Boban;Lynn, Claire;Leung, Anskar Y H;Zuna, Jan;Zaliova, Marketa;Bornhauser, Martin;von Bonin, Malte;Lenhard, Boris;Huang, Suming;Mufti, Ghulam J
• 通讯作者: Mufti, Ghulam J