MOLECULAR TARGETS OF TRANSLOCATION T(4;14) IN MULTIPLE MYELOMA PATHOGENESIS

多发性骨髓瘤发病机制中 T(4;14) 易位的分子靶点

基本信息

批准号：
9187811
负责人：
MICHAEL H TOMASSON
金额：
$ 30.96万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187811
关键词：
13q 13q14 Affect American Antibodies B-Cell Development B-Lymphocytes Biological Assay Bone Marrow Cancer Biology Cancer Control Cancer Etiology Cell Compartmentation Cell Line Cells Cessation of life Chromosomal translocation Chromosomes, Human, Pair 13 Complementary DNA DNA Sequence Data Development Diagnosis Disease Etiology Event Gene Targeting Genes Genetic Hematologic Neoplasms Human Immunodeficient Mouse Injectable Knockout Mice Length Malignant - descriptor Malignant Neoplasms Maps Measures Mediating Messenger RNA MicroRNAs Modeling Molecular Target Mouse Strains Multiple Myeloma Mus Mutation Oncogenes Orphan Oxidative Stress Pathogenesis Patients Phenotype Plasma Protein Binding Domain RB1 gene RNA Binding Reactive Oxygen Species Resistance Retinoblastoma Role Sampling Series Small Nucleolar RNA Small RNA Spleen Structure Structure of germinal center of lymph node Testing Tissues Transformed Cell Line Transplantation United States Untranslated RNA WHSC1 gene cancer type cell growth chemotherapy experimental study histone methyltransferase in vivo insight knock-down mutant non-oncogenic novel novel therapeutic intervention outcome forecast overexpression protein expression public health relevance recombinase-mediated cassette exchange small hairpin RNA transcriptome sequencing tumor

项目摘要

DESCRIPTION (provided by applicant): Multiple Myeloma (MM) is the second most common hematologic malignancy in the United States, diagnosed in approximately 14,500 Americans each year, and is responsible for 2% of all cancer deaths (SEER.cancer.gov). MM is an incurable malignancy of antibody-secreting plasma B-cells whose etiology is poorly understood. Chromosomal translocation t(4;14)(p16.3;q32.33) is associated with shorter overall survival and is found in 15% of MM patients. The candidate oncogene WHSC1 (MMSET) at 4p16.3 encodes a histone methyltransferase over-expressed as a result of the t(4;14) in MM cells. Surprisingly, over-expression of WHSC1 cDNA's failed to transform cell lines or to induce any phenotype when expressed in mice. We identified ACA11, an orphan box H/ACA small nucleolar RNA (snoRNA) encoded hosted within WHSC1 at 4p16.3, to be up-regulated in cell lines and MM patient samples harboring t(4;14). ACA11 modulates oxidative stress, contributes to MM cell growth and confers resistance to chemotherapy. ACA11 is a novel oncogenic non-coding RNA and is also expressed in other cancer types. Mutations that cooperate with t(4;14) in myeloma initiation are unknown, but chromosome 13 deletions (Del(13)) are highly correlated with the t(4;14) in MM. Del(13) is found in 85-94% of patients with t(4;14) and associated with poor prognosis. We mapped a minimally deleted region in MM patient samples to the retinoblastoma (RB1) gene at 13q14. Our model is that ACA11 expression cooperates with RB1 loss to cause poor-prognosis MM. We propose to characterize the role of ACA11 in multiple myeloma. Specific Aim 1: Cooperation between ACA11 and the histone methyltransferase WHSC1. We hypothesize that ACA11 cooperates with MMSET protein expression in myeloma pathogenesis and that WHSC1 histone methyltransferase activity is required for cooperation. We will co-express wild-type WHSC1 or HMT-dead WHSC1 alone or with ACA11 in cell lines and mice. Specific Aim 2: Aim 2: How does ACA11 affect levels of ROS and sensitivity to chemotherapy? What domains and partners of ACA11 are required for these effects? Our data suggest that ACA11 modulates reactive oxygen species and resistance to chemotherapy in myeloma. We will determine which residues of ACA11 are required for this function. We hypothesize that ACA11 RNA binding residues will be dispensable for ACA11's oxidative stress function, but that ACA11's protein-binding domains will be critical. Specific Aim 3: ACA11-mediated malignant transformation in the context of Rb1 deletion. The long arm of chromosome 13 is deleted in 50% of all MM patients, and in 90% of patients with the t(4;14). We hypothesize that RB1 loss cooperates with the t(4;14) in myeloma pathogenesis. We will test the effects of ACA11 and WHSC1 expression on B-cell development, oxidative stress and transformation in the context of Rb1 deficiency. Lastly, we will [identify target genes of t(4;14) by RNA- sequencing patient samples.] A betting understanding of how the t(4;14) contributes to myelomagenesis has broad implications to cancer biology and will facilitate the development of novel therapeutic approaches to patients with poor-prognosis MM.

描述（由申请人提供）：多发性骨髓瘤（MM）是美国第二常见的血液系统恶性肿瘤，每年约有14,500名美国人被诊断出，造成所有癌症死亡的2％（seer.cancer.gov）。 MM是抗体分泌血浆B细胞的无法治愈的恶性肿瘤，其病因对病因的理解很少。染色体易位T（4; 14）（P16.3; Q32.33）与较短的总生存期有关，在15％的MM患者中发现。在4P16.3处的候选癌基因WHSC1（MMSET）编码MM细胞中T（4; 14）导致的组蛋白甲基转移酶过表达。令人惊讶的是，WHSC1 cDNA的过表达无法转化细胞系或在小鼠中表达时诱导任何表型。我们确定了ACA11，这是一个孤儿盒H/ACA小核仁RNA（SNORNA），该小核RNA（SNORNA）编码在WHSC1中以4p16.3的形式托管，将在细胞系和带有t的MM患者样品中上调（4; 14）。 ACA11调节氧化应激，有助于MM细胞的生长，并赋予对化疗的耐药性。 ACA11是一种新型的致癌RNA，也在其他癌症类型中表达。与骨髓瘤启动中T（4; 14）合作的突变尚不清楚，但是13染色体的缺失（DEL（13））与MM中的t（4; 14）高度相关。在85-94％的T（4; 14）患者中发现了DEL（13），并且预后不良。我们在MM患者样品中将最小删除的区域映射到了13q14的视网膜母细胞瘤（RB1）基因。我们的模型是，ACA11表达与RB1损失合作，导致预知MM不良。我们建议表征ACA11在多发性骨髓瘤中的作用。具体目标1：ACA11和组蛋白甲基转移酶WHSC1之间的合作。我们假设ACA11在骨髓瘤发病机理中与MMSET蛋白表达合作，并且需要WHSC1组蛋白甲基转移酶活性才能进行合作。我们将单独或单独使用ACA11在细胞系和小鼠中共表达野生型WHSC1或HMT DEAD WHSC1。特定目标2：目标2：ACA11如何影响ROS水平和对化学疗法的敏感性？这些效果需要哪些ACA11的领域和合作伙伴？我们的数据表明，ACA11调节活性氧和对骨髓瘤化疗的抗性。我们将确定此功能需要哪些ACA11残基。我们假设ACA11 RNA结合残基对于ACA11的氧化应激功能是可分配的，但是ACA11的蛋白质结合结构域至关重要。特定目标3：在RB1缺失的背景下，ACA11介导的恶性转化。在50％的所有MM患者中，染色体13染色体的长臂被删除，其中90％的T患者（4; 14）被删除。我们假设RB1损失与骨髓瘤发病机理中的T（4; 14）合作。我们将在RB1缺乏症的背景下测试ACA11和WHSC1表达对B细胞发育，氧化应激和转化的影响。最后，我们将通过RNA测序患者样品来识别t（4; 14）的靶基因。]对T（4; 14）如何促进骨髓造成的促进对癌症生物学的影响，并将促进对较差的prognopsis MMMM的患者的新型治疗方法的发展。