Project 3: Early detection and prevention of MM progression

项目3：早期发现和预防MM进展

基本信息

批准号：
10706331
负责人：
Marta Chesi
金额：
$ 39.2万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706331
关键词：
Affect Anemia Anti-Inflammatory Agents Automobile Driving BIRC2 gene BRAF gene Benign Blood Bone Marrow CDKN2C gene Cells Chromosome abnormality Chronic Clinic Clinical Clinical Trials Collection Combined Modality Therapy Cytogenetics DNMT3a Data Diagnosis Disease Early Diagnosis Early intervention trials Early treatment Enhancers Enrollment Event FGFR3 gene Genetic Growth Heart Diseases Hematopoiesis Hypercalcemia IL6 gene Immunoglobulin Genes Individual Inflammation Intervention Intervention Trial KRAS2 gene Kidney Failure Lesion Life Lymphoma MAP Kinase Gene MDM2 gene Malignant - descriptor Malignant Neoplasms Molecular Abnormality Monoclonal gammopathy of uncertain significance Multiple Myeloma Mus Mutation Myeloid Cells NF-kappa B NF1 gene Nature Organ Outcome PTPN11 gene Pathway interactions Patients Persons Pharmaceutical Preparations Plasma Cell Neoplasm Plasma Cells Population Prevention Prognosis Proteins RB1 gene Recurrence Reporting Research Risk Role Sampling Subgroup TNF receptor-associated factor 3 TP53 gene TRAF2 gene Time Tumor Burden biobank bone clinical biomarkers cohort disability gene translocation high risk immune modulating agents improved inflammatory marker malignant state mouse model mutant next generation sequencing novel therapeutics pre-clinical prevent progression risk prospective randomized, clinical trials therapeutic target treatment response tumor microenvironment

项目摘要

PROJECT SUMMARY Multiple myeloma (MM) is a malignant plasma cell neoplasm leading to anemia, hypercalcemia, renal insufficiency and bone lesions. It is preceded by a common benign monoclonal plasma cell expansion called monoclonal gammopathy of undetermined significance (MGUS) that shares the same initiating events seen in MM. These include recurrent immunoglobulin gene translocations, and hyperdiploidy. There is a third clinical entity in between these two, smoldering multiple myeloma (SMM), in which there has been more extensive plasma cell expansion than MGUS, but the malignant features of MM are not seen. This project is focused on using genetics to more precisely demarcate benign from malignant plasma cells and develop a patho-genetic definition of MM. We hypothesize that an accumulation of secondary genetic events mark the progression from a benign to malignant state. These events involve a handful of pathways common to many cancers: MYC/MAX, MAPK (NRAS, KRAS, BRAF, FGFR3, PTPN11, NF1), NFKB (TRAF3, TRAF2, CYLD, BIRC2/3, MAPK3K14), TP53/MDM2, RB1/CDKN2C, Others (DIS3, FAM46C). One of these pathways is dysregulated in >95% of MM and <5% of MGUS, and we postulate that individually or in combination they can be used to define malignant plasma cells. There is also increasing evidence of a role of the tumor microenvironment in progression of SMM, and recently clonal hematopoiesis has been associated with increased inflammation, and more rapid progression of MM. We will use next generation sequencing to identify clonal hematopoiesis, and to characterize the genetic events present in patients with MGUS, SMM and MM, and correlate these with the clinical course. We will validate our findings in an independent cohort of patients with SMM enrolled on prospective randomized clinical trials. Ultimately, we hope that a genetic definition will allow both the early detection and prompt treatment of MM, resulting in the prevention of the malignant consequences of MM, and prolonged survival for patients.

项目摘要多发性骨髓瘤（MM）是一种恶性血浆细胞肿瘤，导致贫血，高钙血症，肾脏功能不全和骨骼病变。在此之前是一个称为的常见良性单克隆等离子体细胞膨胀具有不确定意义（MGU）的单克隆性伽马病（MGU）具有与相同的启动事件毫米。这些包括复发性免疫球蛋白基因易位和高二倍体。有第三个临床这两个之间的实体，闷烧多发性骨髓瘤（SMM），其中有更广泛的血浆细胞扩展比MGU，但没有看到MM的恶性特征。该项目的重点是使用遗传学从恶性等离子体细胞中更精确地划分良性并发展病原体 MM的定义。我们假设次级遗传事件的积累标志着来自对恶性国家的良性。这些事件涉及许多癌症常见的途径： MYC/MAX，MAPK（NRAS，KRAS，BRAF，FGFR3，PTPN11，NF1），NFKB（TRAF3，TRAF2，CYLD，CYLD，BIRC2/3， MAPK3K14），TP53/MDM2，RB1/CDKN2C，其他（DIS3，FAM46C）。这些途径之一在 > 95％的MM和<5％的MGU，我们假设单独或组合可以使用它们定义恶性血浆细胞。越来越多的证据表明肿瘤微环境在 SMM的进展以及最近克隆造血的进展与炎症增加有关，并且 MM的更快进展。我们将使用下一代测序来识别克隆造血，并表征MGU，SMM和MM患者中存在的遗传事件，并将其与临床课程。我们将在招募的SMM的独立患者中验证我们的发现前瞻性随机临床试验。最终，我们希望遗传定义将允许早期检测和迅速治疗MM，导致预防MM的恶性后果，并患者长期生存。