Pre-BCR and STAT5 Signaling in Acute Lymphoblastic Leukemia

急性淋巴细胞白血病中的前 BCR 和 STAT5 信号转导

基本信息

批准号：
10319979
负责人：
Michael Archibald Farrar
金额：
$ 36.91万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319979
关键词：
Acute Lymphocytic Leukemia Adult Alleles B Cell Proliferation B cell differentiation B-Cell Acute Lymphoblastic Leukemia B-Cell Development B-Lymphocytes Binding CREBBP gene Cancer Relapse Cause of Death Cell Cycle Cessation of life ChIP-seq Child Childhood Chromatin Complex Data Defect Development Disease Outcome EP300 gene Enhancers Ensure Epigenetic Process Equilibrium Feedback Gene Dosage Genes Genetic Transcription Grant HDAC3 gene Health Histone Deacetylase Human IRF4 gene Lead LoxP-flanked allele Malignant Childhood Neoplasm Malignant Neoplasms Molecular Mus NCOR1 gene Oncogenes PAX5 gene Pathway interactions Patients Play Process Prognosis Role SMARCA4 gene Sampling Signal Transduction Site Stat5 protein Testing Tumor Suppressor Genes Tumor Suppressor Proteins cell transformation chromatin remodeling cohort genetic corepressor genome-wide histone acetyltransferase leukemia mouse model prevent progenitor recruit transcription factor transcriptome sequencing

项目摘要

Project Summary Progenitor B cell acute lymphoblastic leukemia (B-ALL) is the most common form of cancer in children. Although substantial progress has been made in treating children with this form of cancer, relapsed B-ALL still accounts for the highest number of childhood deaths due to cancer. B-ALL is less common in adults but their prognosis is much poorer (~40% survival). Thus, B-ALL remains a significant health challenge. Substantial evidence now exists that activation of the JAK/STAT5 pathway is associated with the development of B-ALL. Likewise, mono-allelic deletions in genes encoding a network of transcription factors required for B cell development, including IKZF1, PAX5 and EBF1, are frequently observed in human B-ALL. We previously established that STAT5 activation cooperates with defects in a pre-BCR pathway that ultimately impinges on a network of transcription factors including PAX5, EBF1, PU.1, IRF4 and IKZF1 (referred to collectively hereafter as PEPII factors) to initiate transformation. Thus, our findings demonstrated that maintaining appropriate balance between STAT5 activation and PEPII factors is important for entraining normal B cell differentiation and preventing B cell transformation. A key question that remains is how these two opposing transcriptional networks function to govern B cell development and leukemia initiation. Our preliminary studies suggest that STAT5 and PEPII bind to nearby sites within super-enhancers and recruit opposing epigenetic modifiers, such as histone acetyltransferases (HATs) and deacetylases (HDACs). Additional preliminary ChIP-Seq data show co-localization between STAT5 and the chromatin remodeler BRG1 at multiple enhancers. We propose that recruitment of specific HATs, HDACS and chromatin remodelers by STAT5 and PEPII factors sequentially alters the enhancer landscape in a manner that promotes normal B cell development. Thus, our underlying hypothesis is that STAT5 and the PEPII transcriptional network are involved in carefully orchestrated feedback loops to ensure both appropriate progenitor B cell expansion, and subsequent exit from cell cycle with differentiation to the small pre-B cell stage. We further propose that perturbations in this network lead to transformation. These hypotheses will be explored in the following two specific aims: (1) Establish the mechanism by which STAT5 alters the enhancer landscape during B cell development and transformation, and (2) Establish how STAT5 and PEPII factors regulate oncogenes during B cell differentiation and transformation. Successful completion of these aims will illuminate how two opposing transcriptional networks function to govern normal B cell development and how perturbing that network allows for both initial progenitor B cell transformation as well as subsequent reversal of the transformation process.

项目概要祖 B 细胞急性淋巴细胞白血病 (B-ALL) 是儿童最常见的癌症形式。尽管在治疗患有这种癌症的儿童方面已经取得了实质性进展，但复发性 B-ALL 仍然因癌症导致的儿童死亡人数最多。 B-ALL 在成人中较少见，但他们预后较差（约 40% 的生存率）。因此，B-ALL 仍然是一个重大的健康挑战。重大的现在有证据表明 JAK/STAT5 通路的激活与 B-ALL 的发生有关。同样，编码 B 细胞所需转录因子网络的基因中的单等位基因缺失包括 IKZF1、PAX5 和 EBF1 在内的发育，经常在人类 B-ALL 中观察到。我们之前确定 STAT5 激活与 BCR 前通路中的缺陷协同作用，最终影响转录因子网络包括 PAX5、EBF1、PU.1、IRF4 和 IKZF1（以下统称为作为 PEPII 因子）来启动转化。因此，我们的研究结果表明，保持适当的 STAT5 激活和 PEPII 因子之间的平衡对于促进正常 B 细胞分化非常重要并阻止 B 细胞转化。剩下的一个关键问题是这两种相反的转录如何网络的功能是控制 B 细胞发育和白血病的发生。我们的初步研究表明 STAT5 和 PEPII 与超级增强子内的附近位点结合并招募相反的表观遗传修饰剂，例如如组蛋白乙酰转移酶 (HAT) 和脱乙酰酶 (HDAC)。其他初步 ChIP-Seq 数据显示 STAT5 和染色质重塑蛋白 BRG1 在多个增强子上的共定位。我们建议通过 STAT5 和 PEPII 因子招募特定的 HAT、HDACS 和染色质重塑因子以促进正常 B 细胞发育的方式依次改变增强子景观。因此，我们的基本假设是 STAT5 和 PEPII 转录网络参与精心策划的反馈循环，以确保祖 B 细胞适当扩增，并且随后退出细胞周期并分化至小前B细胞阶段。我们进一步建议该网络中的扰动会导致转变。这些假设将在以下两个具体目标：（1）建立STAT5改变增强子景观的机制在 B 细胞发育和转化过程中，(2) 确定 STAT5 和 PEPII 因子如何调节 B细胞分化和转化过程中的癌基因。成功完成这些目标将照亮两个相反的转录网络如何发挥作用来控制正常 B 细胞发育以及如何扰乱该网络允许初始祖 B 细胞转化以及随后的逆转转变过程。