Pax5:Hematopoietic Transcription Factor Involved in ALL

Pax5：参与 ALL 的造血转录因子

• 批准号: 8449531
• 负责人: Harold Phillip Koeffler
• 金额: $ 34.34万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449531
• 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.

描述（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。它在转录上激活和抑制大量基因，这些基因允许 B 淋巴细胞发育并阻止分化为 T 淋巴细胞或骨髓细胞。我们通过 SNP 芯片检查了 633 个急性淋巴细胞白血病 (ALL) 样本的 PAX5 改变（469 个儿科病例、70 个儿科复发病例、74 个成人病例和 50 个作为异种移植物生长的 ALL 样本）。 27% 的样本中发生 PAX5 基因组异常，其中包括 26 个 PAX5 与其他 5 个基因之一的融合。该资助的总体目标是了解 ALL 中 PAX5 改变的临床和病理意义。具体目标 1 将确定 ALL 中 PAX5 基因组异常的频率并确定其临床影响。具体目标 2 将定义和理解 ALL 中 PAX5 融合和突变蛋白的异常功能（体外研究）。研究将包括凝胶阻滞和报告基因分析，以及测试这些蛋白质转录激活选定目标基因的能力。将使用两个 PAX5 融合体 [PAX5-ETV6；PAX5-ETV6； PAX5-C20orf112 (C20)] 包括使用 cDNA 微阵列分析和高通量 ChIP 测序研究对 ALL 中 PAX5 融合蛋白的靶基因进行全基因组鉴定。结果的综合验证将使用多种技术。此外，还将确定PAX5融合蛋白对造血细胞分化的影响。具体目标 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通过损害分化、促进特定区室的存活和/或增殖来破坏正常的稳态淋巴细胞生成或造血作用？其次，我们将鉴定与 PAX5 融合蛋白协同诱导 ALL 的次要事件。第三，我们将确定 PAX5 缺失是否影响人类 Ph1+ ALL 异种移植物的进程。总之，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。这些研究对于疾病的分类具有重要意义，提供新的治疗靶点并促进我们对 ALL 发病机制的理解。

项目成果

Lynch syndrome among gynecologic oncology patients meeting Bethesda guidelines for screening.

• DOI: 10.1016/j.ygyno.2009.11.021
• 发表时间: 2010-03
• 期刊: GYNECOLOGIC ONCOLOGY
• 影响因子: 4.7
• 作者: Walsh, Christine S.;Blum, Audra;Walts, Ann;Alsabeh, Randa;Tran, Hang;Koeffler, H. Phillip;Karlan, Beth Y.
• 通讯作者: Karlan, Beth Y.

Human myelogenous leukemia: enhanced clonal proliferation in the presence of phorbol diesters.

• DOI: 10.1182/blood.v57.2.256.bloodjournal572256
• 发表时间: 1981-02
• 期刊: Blood
• 影响因子: 20.3
• 作者: H. Koeffler

Connective tissue growth factor associated with oncogenic activities and drug resistance in glioblastoma multiforme.

• DOI: 10.1002/ijc.25257
• 发表时间: 2010-11-15
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Yin, Dong;Chen, Weikai;O'Kelly, James;Lu, Daning;Ham, Michelle;Doan, Ngan B.;Xie, Dong;Wang, Charles;Vadgama, Jay;Said, Jonathan W.;Black, Keith L.;Koeffler, H. Phillip
• 通讯作者: Koeffler, H. Phillip

Recombinant human tumor necrosis factor alpha regulates c-myc expression in HL-60 cells at the level of transcription.

重组人肿瘤坏死因子 α 在转录水平调节 HL-60 细胞中的 c-myc 表达。

• 发表时间: 1987
• 期刊: Blood
• 影响因子: 20.3
• 作者: Tobler,A;Johnston,D;Koeffler,HP
• 通讯作者: Koeffler,HP

Cimetidine and granulopoiesis: bone marrow culture studies in normal man and patients with cimetidine-associated neutropenia.

西咪替丁和粒细胞生成：正常人和西咪替丁相关中性粒细胞减少症患者的骨髓培养研究。

• DOI: 10.1111/j.1365-2141.1980.tb05982.x
• 发表时间: 1980
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Fitchen,JH;Koeffler,HP
• 通讯作者: Koeffler,HP