Role of senescence in multiple myeloma tumorigenesis

衰老在多发性骨髓瘤肿瘤发生中的作用

• 批准号: 10659259
• 负责人: Thomas Levin Geiser Andersen
• 金额: $ 39.87万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659259
• 关键词: Ablation; Acute; Age; Aging; Area; Automobile Driving; Benign; Benign Monoclonal Gammopathies; Biopsy; Bone Marrow; Cell Aging; Cell Senescence Induction; Cells; Cellular Stress; Characteristics; Chromosome abnormality; Clinical Trials; Clonal Evolution; DNA; DNA Transposable Elements; Data; Data Set; Development; Diagnosis; Disease Progression; Evaluation; Exhibits; Gene Deletion; Gene Expression; Gene Mutation; Genes; Genetic; Genomic Instability; Goals; Growth; Hematologic Neoplasms; Hematopoietic Neoplasms; Human; Hybrids; In Vitro; Incidence; Inflammation; Inflammatory; Interferons; Malignant Neoplasms; Mediating; Methylation; Monoclonal Gammapathies; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mus; Mutation; Nucleic Acids; Obesity; Oncogene Activation; Oncogenes; Oncogenic; Pathology; Patients; Phenotype; Plasma Cell Neoplasm; Plasma Cells; Precancerous Conditions; RNA; Risk Factors; Role; Single-Stranded DNA; Stains; Techniques; Testing; Translating; United States; aged; bone; cell transformation; in vivo; mouse model; neoplastic cell; permissiveness; pharmacologic; premalignant; prevent; promoter; response; senescence; success; therapeutic development; tool; tumor; tumorigenesis; tumorigenic

Abstract Multiple myeloma (MM) is an incurable, plasma cell (PC) malignancy that progresses from the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Although MGUS and SMM PCs exhibit similar oncogenic mutations to MM PCs, they are considered benign and it is unclear what drives tumorigenesis of these pre-malignant PCs. Aging is the primary risk factor for cancers, including MM; it is therefore unsurprising that aging and tumorigenesis exhibit shared mechanisms. One of these shared mechanisms is cellular senescence. Cellular senescence is induced in response to cellular stress, such as oncogenic mutations, and activates growth arrest to prevent tumor formation. However, the accumulation of senescent cells with age contributes to aging pathologies, including cancer. Although deletion or inhibition of genes necessary for senescence induction leads to tumor formation, elimination of senescent cells reduces tumor incidence in aged mice. This suggests that senescent cell accumulation may create a pro- tumorigenic microenvironment; alternatively, pre-tumor cells may themselves be senescent and targeted by senescent cell elimination strategies. In support of this, we found that both MGUS and SMM PCs have enrichment of cellular senescence genes. In addition, SMM PCs show characteristics of late-senescence, including an interferon senescence-associated secretory phenotype (SASP) and the accumulation of cytosolic ssDNA and DNA:RNA hybrids that are associated with increased genomic instability. These findings support a role for PC senescence in monoclonal gammopathies, and suggest a potential mechanism that may ultimately drive tumorigenesis. Importantly, clonal PCs have also been shown to induce senescence in the bone marrow microenvironment (BMME), suggesting additional mechanisms by which senescence may promote a permissive niche for MM tumorigenesis. Thus, we hypothesize that senescence within PCs and their proximate BMME drives progression of MGUS/SMM to MM. In this application, we propose to use genetic mouse models and human patient-derived cells and bone biopsies to ascertain the mechanisms by which senescence drives tumorigenesis through both direct effects on pre-tumor cells and on the BMME. The results of these studies will define a role for senescence, a common aging mechanism, in tumorigenesis. We anticipate that these findings can be rapidly translated to clinical trials targeting the progression of monoclonal gammopathies to MM.

摘要 多发性骨髓瘤(MM)是一种无法治愈的浆细胞(PC)恶性肿瘤，由先兆发展而来 未确定意义的单克隆性伽马病(MGUS)和阴燃多发性骨髓瘤 (SMM)。尽管MGUS和SMM PC表现出与MM PC相似的致癌突变，但它们被认为是 良性的，目前还不清楚是什么推动了这些癌前病变的发生。老龄化是主要的风险因素 对于癌症，包括多发性骨髓瘤；因此，衰老和肿瘤发生呈现共同的机制也就不足为奇了。 这些共同的机制之一是细胞衰老。细胞衰老是对细胞 应激，如致癌基因突变，并激活生长停滞，以防止肿瘤形成。然而， 随着年龄的增长，衰老细胞的积累会导致包括癌症在内的衰老病理。虽然删除了 或抑制衰老诱导所必需的基因会导致肿瘤的形成，消除衰老 细胞可降低老龄小鼠的肿瘤发病率。这表明衰老细胞的积累可能会产生一种促进 肿瘤形成的微环境；或者，肿瘤前细胞本身可能会衰老，并被 消除衰老细胞的策略。为了支持这一点，我们发现MGUS和SMM PC都有 丰富细胞衰老基因。此外，SMM PC还表现出晚衰老的特点， 包括干扰素衰老相关分泌表型(SASP)和胞浆蓄积 单链DNA和DNA：与基因组不稳定性增加相关的RNA杂交体。这些发现支持一种 PC衰老在单克隆性伽马病中的作用，并提出了一种潜在的机制，最终可能 推动肿瘤的形成。重要的是，克隆的pc也被证明可以诱导骨髓衰老。 微环境(BMME)，提示衰老可能促进许可的其他机制 多发性骨髓瘤发生的利基。因此，我们假设PC及其邻近的BMME内的衰老 推动MGUS/SMM向MM发展。在这一应用中，我们建议使用遗传小鼠模型和 人类患者来源的细胞和骨活检以确定衰老驱动的机制 肿瘤的发生通过对肿瘤前细胞和骨髓微血管生成的直接作用来实现。这些研究的结果将 确定衰老在肿瘤发生中的作用，衰老是一种常见的衰老机制。我们预计这些发现 可以迅速转化为针对单克隆性免疫病进展为MM的临床试验。

项目成果

Disturbed bone marrow adiposity in patients with Cushing's syndrome and glucocorticoid- and postmenopausal- induced osteoporosis.

• DOI: 10.3389/fendo.2023.1232574
• 发表时间: 2023
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2

Bone marrow adipocytes provide early sign for progression from MGUS to multiple myeloma.

• DOI: 10.18632/oncotarget.28548
• 发表时间: 2024-01-16
• 期刊: ONCOTARGET
• 作者: El-Masri, Bilal M;Leka, Benedeta;Mustapha, Fatima;Gundesen, Michael Tveden;Hinge, Maja;Lund, Thomas;Andersen, Thomas L;Diaz-delCastillo, Marta;Jafari, Abbas
• 通讯作者: Jafari, Abbas