Molecular pathogenesis of MLL-AF4 leukemias

MLL-AF4 白血病的分子发病机制

• 批准号: 8635305
• 负责人: SCOTT A ARMSTRONG
• 金额: $ 34.52万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635305
• 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 Leukemia; Light; Lymphoblastic Leukemia; Lymphoid; Lysine; MLL gene; MLL-AF9; MLLT2 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

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.

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。

项目成果

The role of DOT1L in the maintenance of leukemia gene expression.

• DOI: 10.1016/j.gde.2016.03.015
• 发表时间: 2016-02
• 期刊: Current opinion in genetics & development
• 影响因子: 4
• 作者: Xi Wang;Chun-Wei Chen;S. Armstrong

Chromatin-modifying enzymes as modulators of reprogramming.

• DOI: 10.1038/nature10953
• 发表时间: 2012-03-04
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Onder, Tamer T.;Kara, Nergis;Cherry, Anne;Sinha, Amit U.;Zhu, Nan;Bernt, Kathrin M.;Cahan, Patrick;Mancarci, B. Ogan;Unternaehrer, Juli;Gupta, Piyush B.;Lander, Eric S.;Armstrong, Scott A.;Daley, George Q.
• 通讯作者: Daley, George Q.