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: 9759647
• 负责人: Jonathan D. Licht
• 金额: $ 33.84万
• 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/9759647
• 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; Genes; Genetic; Genome; Grant; Growth; Hematology; 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.