STAT5 in B cell Acute Lymphoblastic Leukemia

B细胞急性淋巴细胞白血病中的STAT5

• 批准号: 10457259
• 负责人: Robin D. Lee
• 金额: $ 3.59万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-19 至 2023-07-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457259
• 关键词: Adult; Alleles; B Cell Proliferation; B cell differentiation; B-Cell Acute Lymphoblastic Leukemia; B-Cell Development; B-Cell Leukemia; B-Lymphocytes; BCR Signaling Pathway; Binding; Bioinformatics; Biological; CREBBP gene; Cancer Model; Cardiotoxicity; Cause of Death; Cells; ChIP-seq; Child; Clinical; Complex; Data; Data Set; Defect; Disease Outcome; EP300 gene; Enhancers; Equilibrium; Exhibits; Future; Gene Expression; Genes; Genetic Transcription; Genomics; Goals; Health; Histone Deacetylase; Histones; Human; IRF4 gene; Intellectual impairment; Intervention; Lead; LoxP-flanked allele; Malignant Childhood Neoplasm; Mus; NCOR1 gene; NCOR2 gene; Neoplasm Metastasis; Oncogenes; Oncologist; PAX5 gene; Pathway interactions; Patients; Pharmacologic Substance; Play; Process; Prognosis; Relapse; Repression; Repressor Proteins; Role; Sampling; Signal Pathway; Sleeping Beauty; Stat5 protein; Testing; Tumor Suppressor Genes; base; cancer type; cell transformation; cohort; genetic corepressor; histone acetyltransferase; improved; inhibitor; leukemia; novel therapeutics; prevent; progenitor; recruit; skills; transcription factor; transcriptome sequencing; young adult

Project Abstract Progenitor B cell acute lymphoblastic leukemia (B-ALL) is the most common form of childhood cancer. New therapies have substantially improved the prognosis of this type of cancer, yet relapsed B-ALL remains a leading cause of death in children and young adults. Thus, B-ALL remains a significant health challenge. Currently, activation of the JAK/STAT5 pathway is strongly implicated in the development of B-ALL. Likewise, genes encoding a network of transcription factors required for B cell development, including IKZF1, PAX5, and EBF1, are frequently expressed at lower levels in B-ALL due to deletions in one of the alleles encoding these transcription factors. Our lab has shown that STAT5 activation cooperates with defects in the pre-BCR signaling pathway, including PAX5, EBF1, PU.1, IRF4, and IKAROS (collectively referred to as PEPII factors hereafter) to initiate transformation. Therefore, these findings demonstrated that proper balance between STAT5 activation and PEPII factors is important for entraining normal B cell differentiation and preventing B cell transformation. One key question that emerges from these results is how STAT5 activation can alter target gene expression. Our data suggests that active phosphorylated STAT5 can bind to target genes and both activate key oncogenes while repressing tumor suppressor genes. However, the mechanism by which this occurs remains unclear. Based on previous studies and preliminary data, STAT5 can associate with co-activators, such as EP300 and CREBBP, and with co-repressors, such as NCOR1 and NCOR2. I hereby propose that the recruitment of EP300 but not CREBBP is critical for STAT5 to induce transcription of key oncogenes. I further propose that the interaction of STAT5 with the NCOR1 and NCOR2 repressor complex is required for STAT5- dependent repression of tumor suppressor genes. Thus, my central hypothesis is that a proper STAT5 transcriptional network is required for promoting normal B cell development and that perturbation of this network can lead to B cell transformation. These hypotheses will be tested in the following two specific aims (1) Establish the mechanism by which STAT5 regulates the transcription of key oncogenes, and (2) Establish how STAT5 represses transcription of key tumor suppressor genes in progenitor B cell leukemia. The completion of these aims will further advance our understanding of how STAT5 both activates and represses transcription and how subsequent perturbation of these functions can lead to transformation in B-ALL.

项目摘要 祖细胞B细胞急性淋巴细胞白血病（B-ALL）是儿童癌的最常见形式。新的 疗法大大改善了这种类型癌症的预后，但复发的B-均仍然是A 儿童和年轻人的主要死亡原因。因此，B-All仍然是重大的健康挑战。 目前，JAK/STAT5途径的激活与B-all的发展有很大的牵涉。同样地， 编码B细胞开发所需的转录因子网络的基因，包括IKZF1，PAX5和 EBF1，由于编码这些等位基因之一的删除，在B-All中经常以较低的级别表示 转录因子。我们的实验室表明，STAT5激活与前BCR中的缺陷合作 信号通路，包括PAX5，EBF1，PU.1，IRF4和IKAROS（统称为PEPII因子 此后）启动转型。因此，这些发现表明 STAT5激活和PEPII因子对于进入正常B细胞​​分化并防止B很重要 细胞转换。从这些结果中出现的一个关键问题是STAT5激活如何改变目标 基因表达。我们的数据表明，活性磷酸化的STAT5可以与靶基因结合，两者都可以结合 激活关键的致癌基因，同时抑制肿瘤抑制基因。但是，这种机制 发生尚不清楚。根据先前的研究和初步数据，STAT5可以与 诸如EP300和CREBBP之类的共激活因子，以及与NCOR1和NCOR2等共抑制剂。我在那里 提出招募EP300而不是CrebBB对于STAT5诱导转录至关重要 关键的致癌基因。我进一步建议STAT5与NCOR1和NCOR2抑制剂的相互作用 STAT5依赖性抑制肿瘤抑制基因所必需的复合物。因此，我的中心 假设是促进正常B细胞​​需要适当的STAT5转录网络 开发和该网络的扰动会导致B细胞转换。这些假设 将在以下两个具体目的（1）中进行测试 关键致癌基因的转录，以及（2）确定STAT5如何抑制关键肿瘤抑制剂的转录 祖细胞B细胞白血病中的基因。这些目标的完成将进一步提高我们对 STAT5如何激活和压抑转录以及这些功能的随后扰动如何 可以导致B-all中的转换。