Chromatin dysregulation generated by recurrent point mutation in histone methyltransferase, MMSET, drives progression of lymphoid malignancies

组蛋白甲基转移酶（MMSET）反复点突变引起的染色质失调导致淋巴恶性肿瘤的进展

• 批准号: 9051218
• 负责人: Alok Swaroop
• 金额: $ 3.74万
• 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: 2016-06-20 至 2019-06-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9051218
• 关键词: Accounting; Acute Lymphocytic Leukemia; Affect; Alleles; Apoptosis; Biological; Biological Process; CRISPR/Cas technology; Cancer Patient; Cell Adhesion; Cell Cycle Regulation; Cell Line; Cell Proliferation; Cell physiology; Cells; Childhood Acute Lymphocytic Leukemia; Chromatin; Chromatin Structure; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 4; Chronic Lymphocytic Leukemia; DNA; DNA Packaging; DNA Repair; DNA Sequence; DNA biosynthesis; Development; Disease; Disease Progression; EZH2 gene; Epigenetic Process; Fluorescence; Frequencies; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Silencing; Genes; Genome Stability; Histone H3; Investigation; Knock-in; Knowledge; Learning; Link; Lymphocyte; Lymphoid Cell; Lysine; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant lymphoid neoplasm; Mantle Cell Lymphoma; Modeling; Modification; Molecular; Multiple Myeloma; Mus; Mutant Strains Mice; Mutation; Normal Cell; Oncogenes; Oncogenic; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Point Mutation; Positioning Attribute; Pre-B Acute Lymphoblastic Leukemia; Production; Proteins; RNA; Recurrence; Relapse; Research; Sampling; Severity of illness; Spectrum Analysis; Staging; TCF3 gene; Technology; Testing; Time; Tissues; Tumor Suppressor Genes; WHSC1 gene; cancer therapy; cancer type; cell growth; cell motility; combat; design; epigenetic regulation; gain of function; histone methyltransferase; in vivo; inhibitor/antagonist; mouse model; mutant; new therapeutic target; next generation sequencing; outcome forecast; overexpression; personalized medicine; programs; public health relevance; t(1; 19)(q23; p13); targeted cancer therapy; therapeutic target

 DESCRIPTION (provided by applicant): The genes encoded by our DNA form the template for the RNA and proteins that make up our cells and tissues and allow them to carry out their normal functions. However, not all of our DNA is expressed simultaneously by every cell. Epigenetic regulation changes the packaging and handling of DNA, providing genetically identical cells the ability to produce dramatically different patterns of gene expression. It allow for cells and tissues to silence the genes they don't need, and activate the genes they do. Now, advances in sequencing technologies are revealing that epigenetic regulators are among the most frequently altered genes in cancer. In many cancers, these epigenetic regulators do not function properly, often as a result of mutations in their DNA sequence. Our group and others have identified Multiple Myeloma SET domain-containing protein (MMSET) as an important epigenetic regulator in cancer. In normal cells, MMSET modifies the packaging of DNA in specific chromosomal regions to activate expression of genes. However, in many cancers, changes in the MMSET gene result in increased production of MMSET, which can cause increased cell growth and is associated with poor patient prognosis. Recently, a hyperactive form of MMSET was detected in several cancers of lymphoid cells, including relapsed pediatric acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL). This hyperactive form is generated by a single mutation at position 1099 in the MMSET gene (MMSET E1099K). However, the biological function of MMSET E1099K in cancers is not fully understood. We hypothesize that the E1099K mutation leads to alterations in DNA packaging and handling, which results in changes in gene expression and in turn drives progression of lymphoid malignancies. We will test this hypothesis by examining the gene expression changes and biological consequences of the MMSET E1099K mutant in ALL and MCL cells and in mice. The mouse mutant will also help us learn how MMSET collaborates with other important drivers of cancer pathology. These studies will further our knowledge of lymphoid malignancy progression, as well as help us learn how to best design cancer therapies to target epigenetic dysregulation generated by MMSET E1099K.

 描述（由申请人提供）：由我们的DNA编码的基因形成了RNA和蛋白质的模板，这些RNA和蛋白质构成了我们的细胞和组织，并使它们能够发挥正常功能。然而，并不是所有的DNA都能在每个细胞中同时表达。表观遗传调控改变了DNA的包装和处理，使遗传上相同的细胞能够产生截然不同的基因表达模式。它允许细胞和组织沉默它们不需要的基因，并激活它们需要的基因。现在，测序技术的进步揭示了表观遗传调节因子是癌症中最常改变的基因之一。在许多癌症中，这些表观遗传调节因子不能正常发挥作用，通常是由于其DNA序列突变。我们的小组和其他人已经确定多发性骨髓瘤SET域蛋白（MMSET）作为一个重要的表观遗传调节癌症。在正常细胞中，MMSET修饰特定染色体区域的DNA包装以激活基因表达。然而，在许多癌症中，MMSET基因的变化导致MMSET的产生增加，这可能导致细胞生长增加，并与患者预后不良相关。最近，在几种淋巴细胞癌症中检测到MMSET的过度活跃形式，包括复发性小儿急性淋巴细胞白血病（ALL）、慢性淋巴细胞白血病（CLL）和套细胞淋巴瘤（MCL）。这种过度活跃的形式是由MMSET基因（MMSET E1099K）中位置1099处的单个突变产生的。然而，MMSET E1099K在癌症中的生物学功能尚未完全了解。我们假设E1099K突变导致DNA包装和处理的改变，从而导致基因表达的变化，进而驱动淋巴恶性肿瘤的进展。我们将通过研究ALL和MCL细胞以及小鼠中MMSET E1099K突变体的基因表达变化和生物学后果来验证这一假设。小鼠突变体还将帮助我们了解MMSET如何与癌症病理学的其他重要驱动因素合作。这些研究将进一步加深我们对淋巴恶性肿瘤进展的了解，并帮助我们了解如何最好地设计癌症治疗方案，以靶向MMSET E1099K产生的表观遗传失调。