Pax5:Hematopoietic Transcription Factor Involved in ALL

Pax5：参与 ALL 的造血转录因子

• 批准号: 8256532
• 负责人: Harold Phillip Koeffler
• 金额: $ 36.53万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256532
• 关键词: Acute; Acute Lymphocytic Leukemia; Acute leukemia; Adult; Affect; B cell differentiation; B-Lymphocytes; Biology; Cell Differentiation process; Cells; ChIP-seq; Characteristics; Childhood; Chimeric Proteins; Clinical; Development; ETV6 gene; Event; Fostering; Frequencies; Gel; Gene Targeting; Genes; Genetic; Genomics; Goals; Grant; Hematopoiesis; Hematopoietic; Human; Lead; Lymphocyte; Lymphoid; Lymphopoiesis; Mediating; Microarray Analysis; Mutation; Myeloid Cells; PAX5 gene; Pathogenesis; Pathologic; Patients; Proteins; Relapse; Reporter Genes; Sampling; T-Lymphocyte; Techniques; Testing; Time; Validation; Xenograft procedure; cDNA Arrays; clinically significant; disease classification; genome wide association study; in vivo Model; insight; leukemia; mutant; new therapeutic target; prevent; public health relevance; transcription factor

DESCRIPTION (provided by applicant): PAX5 is one of the key transcription factors mediating differentiation of B-lymphocytes. It transcriptionally activates and represses a very large number of genes that permits the development of B-lymphocytes and prevents differentiation to T-lymphocytes or myeloid cells. We examined by SNP chip 633 acute lymphocytic leukemia (ALL) samples for PAX5 alterations (469 pediatric cases, 70 pediatric relapse cases, 74 adult cases and 50 ALL samples growing as xenografts). PAX5 genomic abnormalities occurred in H 27% of the samples including 26 PAX5 fusions to one of 5 other genes. Overall goal of the grant is to understand the clinical and pathologic significance of PAX5 alterations in ALL. Specific Aim 1 will determine frequency of genomic abnormalities of PAX5 in ALL and determine their clinical impact. Specific Aim 2 will define and understand the aberrant functions of PAX5 fusion and mutant proteins in ALL (Ex Vivo Studies). Studies will include gel retardation and reporter gene analysis as well as testing the ability of these proteins transcriptionally to activate selected target genes. Detailed studies will be done using two of the PAX5 fusions [PAX5-ETV6; PAX5- C20orf112 (C20)] including genome-wide identification of target genes of PAX5 fusion proteins in ALL using cDNA microarray analysis and high through-put ChIP sequencing studies. Comprehensive validation of the results will use a variety of techniques. Also, effect of PAX5 fusion proteins on hematopoietic cell differentiation will be determined. Specific Aim 3 will use in vivo models to examine the aberrant function of PAX5 fusions and deletions. First, we will determine if expression of PAX5 fusion proteins disrupts normal steady-state lymphopoiesis or hematopoiesis by impairing differentiation, promoting survival and/or proliferation of specific compartments? Second, we will identify secondary events that synergize with PAX5 fusion proteins to induce ALL. Third, we will determine if PAX5 deletions affect the course of human Ph1+ ALL xenografts. In summary, we will for the first time, correlate PAX5 alterations with clinical and pathological characteristics of the patients and define fully the functional significance of these alterations. These studies will have importance for classification of the disease, offer new therapeutic targets and foster our understanding of the pathogenesis of ALL. PUBLIC HEALTH RELEVANCE: PAX5 lymphoid transcription factor is structurally abnormal in approximately 27% of 634 ALL samples. Our studies will for the first time provide insights into the clinical significance of PAX5 alterations in acute lymphocyte leukemia (ALL), as well as provide an understanding of the functional ramifications of PAX5 alterations in ALL. Our studies should lead to new therapeutic targets for acute leukemias, as well as provide a greater understanding of the biology of ALL.

描述（由申请人提供）：PAX5是介导B淋巴细胞分化的关键转录因子之一。它在转录上激活并抑制了大量基因，这些基因允许B淋巴细胞的发展，并防止分化与T淋巴细胞或髓样细胞的分化。我们通过SNP芯片633急性淋巴细胞性白血病（所有）样品进行了检查（469例小儿病例，70例儿科复发病例，74例成人病例，50例所有样本作为异种移植）。 PAX5基因组异常发生在H 27％的样品中，包括26个PAX5融合到其他5个基因之一。该赠款的总体目标是了解PAX5改变的临床和病理意义。具体的目标1将确定所有PAX5基因组异常的频率，并确定其临床影响。特定的目标2将在所有（体内研​​究）中定义和了解PAX5融合和突变蛋白的异常功能。研究将包括凝胶延迟和报告基因分析，并测试这些蛋白在转录上激活所选靶基因的能力。详细的研究将使用两个PAX5融合[PAX5-ETV6； PAX5-C20ORF112（C20）]，包括使用cDNA微阵列分析和高贯穿芯片测序研究的所有基因组鉴定PAX5融合蛋白的靶基因。对结果的全面验证将使用各种技术。同样，将确定PAX5融合蛋白对造血细胞分化的影响。特定的目标3将使用体内模型来检查PAX5融合和缺失的异常功能。首先，我们将确定PAX5融合蛋白的表达是否会通过损害分化，促进特定区室的生存和/或增殖来破坏正常的稳态淋巴房或造血？其次，我们将确定与PAX5融合蛋白协同作用以诱导所有事件的次要事件。第三，我们将确定PAX5缺失是否影响人类PH1+所有异种移植物的过程。总而言之，我们将首次将PAX5改变与患者的临床和病理特征相关联，并充分定义这些改变的功能意义。这些研究将对疾病的分类，提供新的治疗靶标并促进我们对所有人的发病机理的理解。公共卫生相关性：PAX5淋巴转录因子在634个样品中约有27％在结构上异常。我们的研究将首次提供有关PAX5急性淋巴细胞白血病（ALL）PAX5改变的临床意义的见解，并提供了对PAX5改变的功能分析的理解。我们的研究应导致急性白血病的新治疗靶标，并对所有人的生物学有更深入的了解。