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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.

项目总结