The Role of MMSET in the Pathogenesis and Progression of Lymphoid Malignancy

MMSET 在淋巴恶性肿瘤发病机制和进展中的作用

• 批准号: 9330809
• 负责人: Jonathan D. Licht
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-11 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330809
• 关键词: Acute Lymphocytic Leukemia; Affect; Alleles; Animal Disease Models; B-Cell Development; B-Lymphocytes; Binding; Biological; CRISPR/Cas technology; Cell Line; Cell model; Child; Childhood Acute Lymphocytic Leukemia; Chromatin; Chronic Lymphocytic Leukemia; DNA Repair; Data; Development; Disease; Disease Progression; EZH2 gene; Epithelial; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genome; Grant; Growth; Histone-Lysine N-Methyltransferase; Histones; Immunoglobulins; In Vitro; Knock-in; Knock-in Mouse; Lead; Link; Lysine; MYC gene; Malignant Neoplasms; Malignant lymphoid neoplasm; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mantle Cell Lymphoma; Mediating; Mesenchymal; Modeling; Molecular; Multiple Myeloma; Mutate; Mutation; Neuroblastoma; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Point Mutation; Property; Prostate; Proteins; Recurrence; Relapse; Role; SET Domain; Transferase; WHSC1 gene; base; c-myc Genes; cancer cell; cancer therapy; cell growth; cell motility; cell transformation; chromatin modification; gain of function mutation; genetically modified cells; genome sequencing; histone methylation; in vivo; inhibitor/antagonist; molecular sequence database; mouse model; mutant; novel therapeutics; overexpression; prostate cancer cell; public health relevance; response; therapeutic target; tumor

 DESCRIPTION (provided by applicant): We have studied the MMSET (also known as WHSC1 or NSD2) protein a histone lysine methyltransferase identified by its rearrangement with the immunoglobulin locus aberrant overexpression in multiple myeloma (MM). Overexpression of MMSET leads to dramatic shifts in chromatin modification and gene expression and stimulates cell growth. MMSET overexpression has also been linked to aberrant cell growth and invasive properties in prostate, lung cancer and neuroblastoma. More recently we and others described a recurrent point mutation (E1099K) in the SET domain of MMSET in acute lymphoblastic leukemia (ALL). The importance of this mutation is growing as genome sequencing showed that this mutation in present in ~10% of cases of mantle cell lymphoma (MCL) and is found in ~10-20% of cases of relapsed pediatric ALL. Collectively these data indicate that MMSET and the pathways it regulates represent therapeutic targets in MM and other malignancies. Our overarching hypothesis is that overexpression or gain of function mutations of MMSET alter gene regulation leading to the pathogenesis of MM and to the progression of ALL. While some target genes may be activated in common across these tumors, our preliminary data suggests that MMSET mutation dysregulates a unique set of genes in ALL. By constructing genetically engineered cell line and mouse models of models of the action of the E1099K mutation we will ascertain the detailed molecular mechanisms, by which MMSETE1099K affects gene expression, identify critical target genes and pathways and uncover new therapeutic opportunities for cancer treatment. Our specific aims will be: Aim 1: Evaluate the Biological Activity of a Recurrent Point Mutation of MMSET in Malignancy. We will determine the mechanism of action of this protein and how it alters histone methylation levels. Using newly prepared CRISPR/CAS9 edited cell lines we will determine how mutant MMSET modulates cell growth and response to therapy. Aim 2: Define the Genetic Targets and Pathways Affected by Oncogenic Mutations of MMSET. Preliminary data suggest that mutant MMSET activates a different set of genes in ALL compared to those affected in MM. Using genetically edited cell lines, we will determine how the mutation alters chromatin configuration across the genome and identify critical genes and pathways of its oncogenic action. Aim 3: Evaluate the Ability of Mutant MMSET to Collaborate with Known MM and ALL Oncogenes. We will cross a newly created knockin mouse expressing MMSETE1099K with established mouse models of ALL and MM to determine how this disease allele may drive pathogenesis and progression of disease.

 描述（由申请人提供）：我们研究了 MMSET（也称为 WHSC1 或 NSD2）蛋白，这是一种组蛋白赖氨酸甲基转移酶，通过其与多发性骨髓瘤 (MM) 中免疫球蛋白基因座异常过度表达的重排来鉴定。染色质修饰和基因表达以及刺激细胞生长也与异常细胞生长和侵袭特性有关。最近，我们和其他人描述了急性淋巴细胞性前列腺白血病（ALL）中 MMSET 的 SET 结构域中的复发性点突变（E1099K），因为基因组测序表明这种突变的重要性正在增加。约 10% 的套细胞淋巴瘤 (MCL) 病例中存在这种情况，约 10-20% 的复发性儿童 ALL 病例中也存在这种情况，这些数据共同表明 MMSET 及其途径。我们的总体假设是，MMSET 的过度表达或功能突变改变基因调控，导致 MM 的发病机制和 ALL 的进展，而某些靶基因可能在这些肿瘤中被共同激活。我们的初步数据表明，MMSET 突变使 ALL 中的一组独特基因失调。通过构建 E1099K 突变作用的基因工程细胞系和小鼠模型，我们将确定详细的分子机制。我们将确定 MMSETE1099K 影响基因表达的机制，识别关键靶基因和途径，并发现癌症治疗的新治疗机会： 目标 1：评估 MMSET 复发点突变在恶性肿瘤中的生物活性。该蛋白的作用机制以及它如何改变组蛋白甲基化水平，使用新制备的 CRISPR/CAS9 编辑细胞系，我们将确定突变 MMSET 如何调节细胞生长和对治疗的反应。目标 2：确定受 MMSET 致癌突变影响的遗传靶点和途径 初步数据表明，与 MM 中受影响的基因相比，突变 MMSET 在 ALL 中激活了一组不同的基因，我们将确定突变如何改变。目标 3：评估突变 MMSET 与已知的协作能力。 MM 和 ALL 癌基因。我们将新创建的表达 MMSETE1099K 的敲入小鼠与已建立的 ALL 和 MM 小鼠模型进行杂交，以确定该疾病等位基因如何驱动疾病的发病机制和进展。