STAT5 in B cell Acute Lymphoblastic Leukemia

B细胞急性淋巴细胞白血病中的STAT5

基本信息

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
项目类别：
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

项目摘要

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 B 细胞急性淋巴细胞白血病 (B-ALL) 是最常见的儿童癌症。新的治疗已显着改善了此类癌症的预后，但复发性 B-ALL 仍然是一个常见问题儿童和年轻人死亡的主要原因。因此，B-ALL 仍然是一个重大的健康挑战。目前，JAK/STAT5 通路的激活与 B-ALL 的发展密切相关。同样地，编码 B 细胞发育所需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缺失，在 B-ALL 中经常以较低水平表达转录因子。我们的实验室已表明 STAT5 激活与前 BCR 中的缺陷协同作用信号通路，包括PAX5、EBF1、PU.1、IRF4和IKAROS（统称为PEPII因子）下文）启动转型。因此，这些发现表明，两者之间的适当平衡 STAT5 激活和 PEPII 因子对于引导正常 B 细胞分化和预防 B 细胞分化非常重要。细胞转化。这些结果中出现的一个关键问题是 STAT5 激活如何改变靶标基因表达。我们的数据表明，活性磷酸化 STAT5 可以与靶基因结合，并且激活关键癌基因，同时抑制抑癌基因。然而，这种机制发生情况仍不清楚。根据之前的研究和初步数据，STAT5可以与共激活因子，例如 EP300 和 CREBBP，以及共抑制因子，例如 NCOR1 和 NCOR2。我特此认为招募 EP300 而不是 CREBBP 对于 STAT5 诱导转录至关重要关键癌基因。我进一步提出 STAT5 与 NCOR1 和 NCOR2 阻遏蛋白的相互作用 STAT5 依赖性肿瘤抑制基因的抑制需要复合物。因此，我的中心假设认为促进正常 B 细胞需要适当的 STAT5 转录网络发育，并且该网络的扰动可以导致 B 细胞转化。这些假设将在以下两个具体目标上进行测试（1）建立STAT5调节的机制关键癌基因的转录，以及 (2) 确定 STAT5 如何抑制关键肿瘤抑制基因的转录祖B细胞白血病的基因。这些目标的完成将进一步加深我们对 STAT5 如何激活和抑制转录以及这些功能的后续扰动可以导致 B-ALL 的转化。