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（由适用提供）：我们研究了MMSET（也称为WHSC1或NSD2）蛋白A组蛋白赖氨酸甲基转移酶通过其重排与免疫球蛋白基因座的重排在多发性骨髓瘤（MM）中异常表达。 MMSET的过表达导致染色质修饰和基因表达的急剧变化，并刺激细胞生长。 MMSET的过表达也与前列腺，肺癌和神经母细胞瘤的细胞生长和侵入性特性有关。最近，我们和其他人描述了急性淋巴细胞白血病（ALL）中MMSET的固定结构域的复发点突变（E1099K）。这种突变的重要性正在增长，因为基因组测序表明，在约10％的地幔细胞淋巴瘤（MCL）中，这种突变存在于约10-20％的复发儿科病例中。这些数据共同表明MMSET及其调节的途径代表MM和其他恶性肿瘤中的治疗靶标。我们的总体假设是，MMSET的过表达或功能突变改变基因调节导致MM发病机理和所有人的进展。尽管某些靶基因可以在这些肿瘤中共有激活，但我们的初步数据表明，MMSET突变在所有肿瘤中均不足一组独特的基因。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MMSET1099K会影响基因表达，识别关键靶基因和途径的详细分子机制，并发现新的治疗机会用于癌症治疗。我们的具体目的是：目标1：评估恶性肿瘤复发点突变的生物学活性。我们将确定该蛋白质的作用机理以及它如何改变组蛋白甲基化水平。使用新准备的CRISPR/CAS9编辑的细胞系，我们将确定突变体MMSET如何调节细胞生长和对治疗的反应。 AIM 2：定义受MMSET致癌突变影响的遗传靶标和途径。初步数据表明，与在MM中受影响的基因相比，突变体MMSET在所有基因中都激活了不同的基因。使用遗传编辑的细胞系，我们将确定突变如何改变整个基因组的染色质构型，并确定其致癌作用的关键基因和途径。 AIM 3：评估突变MMSET与已知MM和所有癌基因合作的能力。我们将跨越新创建的敲蛋白小鼠，表达MMSETE1099K，并具有所有的所有小鼠模型和MM的模型，以确定该疾病等位基因如何驱动疾病的发病机理和进展。