Molecular Targeting of MLL and Associated Factors

MLL 的分子靶向及相关因素

• 批准号: 8449721
• 负责人: MICHAEL L CLEARY
• 金额: $ 28.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-05 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449721
• 关键词: Achievement; Acute leukemia; Address; Adult; Award; Biochemical; Biochemical Genetics; Biological Models; Cancer Etiology; Cancerous; Cell Line; Cells; Child; Chimeric Proteins; Chromatin; Chromosomal translocation; Clinical; Code; Complex; Elongation Factor; Gene Targeting; Genetic; Genetic Models; HIV; Hematopoietic Neoplasms; Human; Infant; Investigation; Ligands; Link; Lysine; MLL gene; MLLT2 gene; Malignant Neoplasms; Mediating; Menin; Methyltransferase; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mutate; Mutation; Myeloid-Lymphoid Leukemia Protein; Oncogene Proteins; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patients; Physiological; Positive Transcriptional Elongation Factor B; Process; Property; Proteins; Proto-Oncogenes; Role; Stem cells; Techniques; Therapeutic; Transcription Elongation; Transcriptional Regulation; Treatment Protocols; Tumor Suppressor Proteins; alpha-Thalassemia; base; biochemical model; cancer stem cell; histone methyltransferase; intermolecular interaction; leukemia; leukemogenesis; mortality; novel; outcome forecast; pre-clinical; protein complex; public health relevance; response; standard care; transcriptional coactivator p75; tumor

DESCRIPTION (provided by applicant):The Mixed Lineage Leukemia (MLL) gene codes for a histone methyltransferase that is frequently mutated by chromosomal translocations in human leukemias associated with a poor clinical outcome. The studies proposed in this competitive renewal application address the hypothesis that the leukemogenic actions of MLL oncoproteins are critically dependent on proteins recently discovered to associate with MLL or its fusion partners, and that the activities or interactions of these associated factors constitute potential targets for molecular therapies. This hypothesis is based on major discoveries during the current award period that have substantially advanced our understanding of the molecular mechanisms of MLL leukemias. We have shown that menin, a tumor suppressor protein and MLL- associated factor, is paradoxically required for MLL-mediated leukemogenesis. Menin functions as a transcriptional co-factor for MLL oncoproteins, and in this capacity we demonstrated that its only role is to promote interactions with a newly discovered MLL- associated protein known as LEDGF/p75. The latter is a chromatin-associated protein with co-activator activity but unknown molecular function, previously implicated in leukemia and HIV pathogenesis. Studies in the first specific aim will characterize the molecular functions of LEDGF/p75 required for MLL-mediated leukemogenesis using biochemical and genetic approaches in pre-clinical and cell line transformation model systems. These studies will identify a potential ligand for the putative methyl-lysine recognition motif of LEDGF/p75 and also establish the feasibility of antagonizing their interactions as a molecular therapeutic strategy. Studies in the second aim will employ genetic and biochemical techniques to determine the molecular mechanisms that underlie oncogenic activation of LEDGF/p75 itself by chromosomal translocations in leukemias, and establish its specific roles in leukemogenesis mediated through the MLL and/or Myc transcriptional pathways. Studies in the third specific aim are based on our discovery of a multi-protein complex (AEP) that contains several MLL fusion partners and the P-TEFb transcription elongation factor. This novel complex is tethered by a subset of MLL oncoproteins to critical target genes in MLL leukemia cells, however its molecular contributions required for leukemogenesis have not been fully defined. Our studies will further characterize the AEP complex, its critical enzymatic activities, its implications for MLL transcriptional regulation in general, and its role in MLL-mediated leukemogenesis. The therapeutic value of targeting the activities or interactions of AEP components with pathogenic roles in MLL leukemia will be interrogated using preclinical transformation models.

描述（由申请方提供）：混合谱系白血病（MLL）基因编码一种组蛋白甲基转移酶，该基因在人类白血病中经常因染色体易位而突变，临床结局较差。本竞争性更新申请中提出的研究解决了以下假设：MLL癌蛋白的致白血病作用严重依赖于最近发现的与MLL或其融合伴侣相关的蛋白质，并且这些相关因子的活性或相互作用构成了分子治疗的潜在靶点。 这一假设是基于本奖项期间的重大发现，这些发现大大提高了我们对MLL白血病分子机制的理解。我们已经表明，menin，一种肿瘤抑制蛋白和MLL相关因子，是MLL介导的白血病发生所必需的。Menin作为MLL癌蛋白的转录辅因子发挥作用，并且在这种能力下，我们证明了其唯一的作用是促进与新发现的称为LEDGF/p75的MLL相关蛋白的相互作用。后者是一种染色质相关蛋白，具有共激活剂活性，但分子功能未知，以前与白血病和HIV发病机制有关。 第一个具体目标的研究将在临床前和细胞系转化模型系统中使用生物化学和遗传学方法表征MLL介导的白血病发生所需的LEDGF/p75的分子功能。这些研究将确定潜在的LEDGF/p75的甲基赖氨酸识别基序的配体，并建立拮抗它们的相互作用作为分子治疗策略的可行性。 第二个目标的研究将采用遗传和生物化学技术来确定白血病中染色体易位导致LEDGF/p75本身致癌激活的分子机制，并确定其在通过MLL和/或Myc转录途径介导的白血病发生中的特定作用。 第三个具体目标的研究是基于我们发现的多蛋白复合物（AEP），其中包含几个MLL融合伴侣和P-TEFb转录延伸因子。这种新的复合物是由MLL癌蛋白的一个子集拴系到MLL白血病细胞中的关键靶基因，然而，白血病发生所需的分子贡献尚未完全确定。我们的研究将进一步表征AEP复合物，其关键的酶活性，其对MLL转录调控的影响，以及其在MLL介导的白血病发生中的作用。将使用临床前转化模型来询问靶向AEP组分的活性或相互作用与MLL白血病中的致病作用的治疗价值。