Molecular pathogenesis of MLL-AF4 leukemias

MLL-AF4 白血病的分子发病机制

基本信息

批准号：
7886077
负责人：
SCOTT A ARMSTRONG
金额：
$ 35.57万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7886077
关键词：
11q23 Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Address Cell Line Cell Maintenance Cell Survival Cell physiology Cells Chromosomal translocation Commit DNA Sequence Rearrangement Development Diagnosis Disease Evaluation Excision Gene Expression Goals Growth and Development function Hematopoiesis Hematopoietic Hematopoietic stem cells Histone H3 Histones Human In Vitro Infant Light Lymphoblastic Leukemia Lymphoid Lysine MLL gene Mediating Methylation Modeling Modification Molecular Molecular Profiling Mus Pathogenesis Patients Reporting Role Sampling Therapeutic Ursidae Family cell type chromatin modification genome-wide histone methyltransferase in vivo leukemia mouse model novel therapeutic intervention outcome forecast progenitor programs public health relevance recombinase research study retroviral transduction small hairpin RNA therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Acute leukemias that bear chromosomal translocations at 11q23 possess rearrangements of the Mixed Lineage Leukemia gene (MLL, HRX, ALL-1). More than 40 different MLL translocations have been reported, but the t(4;11) (MLL-AF4) is particularly common in leukemias diagnosed as ALL or mixed-lineage leukemia. Patients with MLL-AF4 leukemias have a poor prognosis. This is particularly true for infant leukemia where approximately 80% of cases will harbor rearrangement of the MLL gene. We have recently developed a conditional mouse model of Mll-AF4 ALL that recapitulates the gene expression profiles and histone methylation profiles of human MLL-AF4 ALL. Experiments described in this proposal will build upon these previous studies and characterize leukemia development with a particular focus on histone methylation. We will determine which cell types are permissive for Mll-AF4 leukemia development including hematopoietic stem cells (HSC) and early lymphoid committed cells. We will also determine if MLL-AF4 leukemia cell survival is dependent upon the histone methyltransferase Dot1L. These studies will provide a highly detailed characterization of the cells of origin of Mll-AF4 ALL, and begin to determine if histone methyltransferases are potential therapeutic targets in this disease. PUBLIC HEALTH RELEVANCE: The MLL-AF4 translocation is found in acute lymphoblastic leukemias that confer a poor prognosis. We will use sophisticated mouse models and human leukemia cells, to characterize the abberant molecuar and cellular processes that are induded during leukemia development, and determine if inhibition of specific histone methyltransferases could be a therapeutic target in this disease.

描述（由申请人提供）：11q23 处发生染色体易位的急性白血病具有混合谱系白血病基因（MLL、HRX、ALL-1）的重排。已报道超过 40 种不同的 MLL 易位，但 t(4;11) (MLL-AF4) 在诊断为 ALL 或混合谱系白血病的白血病中尤其常见。 MLL-AF4 白血病患者预后较差。对于婴儿白血病尤其如此，其中大约 80% 的病例会出现 MLL 基因重排。我们最近开发了 Mll-AF4 ALL 的条件小鼠模型，它概括了人类 MLL-AF4 ALL 的基因表达谱和组蛋白甲基化谱。本提案中描述的实验将建立在这些先前的研究的基础上，并表征白血病的发展，特别关注组蛋白甲基化。我们将确定哪些细胞类型适合 Mll-AF4 白血病的发展，包括造血干细胞 (HSC) 和早期淋巴定型细胞。我们还将确定 MLL-AF4 白血病细胞的存活是否依赖于组蛋白甲基转移酶 Dot1L。这些研究将提供 Mll-AF4 ALL 起源细胞的高度详细特征，并开始确定组蛋白甲基转移酶是否是该疾病的潜在治疗靶点。公众健康相关性：MLL-AF4 易位见于急性淋巴细胞白血病，预后不良。我们将使用复杂的小鼠模型和人类白血病细胞来表征白血病发展过程中出现的异常分子和细胞过程，并确定特定组蛋白甲基转移酶的抑制是否可以成为该疾病的治疗靶点。