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

• 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
• 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

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.

项目摘要 祖细胞B细胞急性淋巴细胞白血病（B-All）是儿童中最常见的癌症形式。 尽管在治疗这种形式的癌症的儿童方面取得了重大进展，但复发的B-所有人仍然 造成癌症造成的儿童死亡人数最多。 B-所有人在成年人中不太常见，但他们的 预后较差（生存期约40％）。因此，B-All仍然是重大的健康挑战。重大的 现在有证据表明，JAK/STAT5途径的激活与B-all的发展有关。 同样，在编码B细胞所需的转录因子网络的基因中的单相关缺失 在人类B-all中经常观察到包括IKZF1，PAX5和EBF1在内的开发。我们以前 确定STAT5激活与BCR前途径中的缺陷合作，该途径最终影响 转录因素网络，包括PAX5，EBF1，PU.1，IRF4和IKZF1（以下称为集体称为 作为pepii因素）以启动转化。因此，我们的发现表明保持适当 STAT5激活和PEPII因子之间的平衡对于进入正常B细胞​​分化很重要 并防止B细胞转化。仍然存在的一个关键问题是这两个相对的转录如何 网络功能来控制B细胞发育和白血病的起始。我们的初步研究表明 STAT5和PEPII与超级增强剂内的附近地点结合，并招募相反的表观遗传修饰符，例如 作为组蛋白乙酰转移酶（帽子）和脱乙酰基酶（HDACS）。其他初步芯片播出数据显示 STAT5和染色质重塑剂BRG1在多个增强子处的共定位。我们提出了这一点 通过STAT5和PEPII因子募集特定的帽子，HDAC和染色质重塑剂 依次以促进正常B细胞​​发育的方式改变增强子景观。 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，以确保适当的祖细胞B细胞扩展和 随后从细胞周期退出，分化为小-B细胞阶段。我们进一步提出 该网络中的扰动导致转换。这些假设将在 以下两个具体目的：（1）建立STAT5改变增强剂景观的机制 在B细胞开发和转化期间，以及（2）确定STAT5和PEPII因素如何调节 B细胞分化和转化过程中的癌基因。这些目标的成功完成将阐明 两个相对的转录网络如何控制正常的B细胞开发以及如何扰动 该网络允许初始祖细胞B细胞转换以及随后的逆转 转换过程。