Credentialing a Genetically Engineered Clinically-Relevant Mouse Model of Multiple Myeloma

认证基因工程临床相关的多发性骨髓瘤小鼠模型

• 批准号: 10527365
• 负责人: Marta Chesi
• 金额: $ 37.21万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-07 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527365
• 关键词: Address; Amino Acid Sequence; Anemia; B-Lymphocytes; Bacterial Artificial Chromosomes; Binding; Biological; Biological Models; Biology; Bone Diseases; Bone Marrow; Breeding; Cell Line; Cell Survival; Cell Transplantation; Cells; Clinical; Combination Drug Therapy; Combined Modality Therapy; Complex; Credentialing; Dependence; Drug Receptors; Drug resistance; Drug usage; Engineering; Engraftment; Generations; Genes; Genetic; Genetic Engineering; Genomic approach; Glucocorticoids; Goals; Hematologic Neoplasms; Home; Human; Human Characteristics; Immune system; Immunocompetent; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulins; Immunotherapy; Impairment; Indolent; Interferon Type II; Kidney; Mediating; Modeling; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mus; Mutation; Newly Diagnosed; Patients; Pharmaceutical Preparations; Population; Pre-Clinical Model; Precancerous Conditions; Predictive Value; Proteasome Inhibitor; Publishing; Refractory; Regulatory Element; Relapse; Research Personnel; Resistance; Role; Splenocyte; Structure of germinal center of lymph node; T-Cell Proliferation; Thalidomide; Transcription Factor 3; Transgenic Mice; Transplantation; Ubiquitin; Validation; Variant; Vertebral column; Work; clinical practice; clinical predictors; clinically relevant; drug-sensitive; experimental study; gene product; genetic manipulation; human disease; immune modulating agents; in vivo; in vivo Model; lenalidomide; mouse model; neoplasm immunotherapy; neoplastic cell; novel; plasma cell differentiation; pleiotropism; pomalidomide; post-transplant; receptor; recruit; relapse patients; response; tumor; tumor immunology; tumor progression

Project Summary/Abstract Thalidomide (Thal) and its derivatives, Lenalidomide (Len) and Pomalidomide (POM), are immune modulatory drugs (IMiDs) used in the treatment of multiple myeloma (MM) and few other hematological malignancies. Although they represent the backbone treatment for both newly diagnosed and relapse/refractory MM patients, their clinical use remains mostly empirical because of lack of suitable in vivo model systems to study their complex mechanisms of action. Murine cells are intrinsically resistant to IMiDs because of different amino acid sequence in the IMiD binding domain of cereblon (CRBN). By building upon our extensively validated Vk*MYC transgenic mouse model of MM, we have generated a novel transgenic mouse, Vk*MYChCRBN, expressing the full human CRBN (hCRBN) gene under the control of its endogenous regulatory elements, rendering it IMiD sensitive. As previously done for the Vk*MYC model, we will extensively characterize the new Vk*MYChCRBN model and will use it to understand the IMiD effects on the tumor and the immune system with the ultimate goal to inform clinical practice.

项目概要/摘要 沙利度胺 (Thal) 及其衍生物来那度胺 (Len) 和泊马度胺 (POM) 具有免疫能力 用于治疗多发性骨髓瘤 (MM) 和少数其他疾病的调节药物 (IMiD) 血液系统恶性肿瘤。尽管它们代表了新疗法的骨干治疗 对于已诊断的和复发/难治性 MM 患者，其临床应用仍然主要是经验性的，因为 缺乏合适的体内模型系统来研究其复杂的作用机制。小鼠细胞是 由于 IMiD 结合域中的氨基酸序列不同，因此对 IMiD 具有内在抗性 大脑（CRBN）。通过建立我们广泛验证的 Vk*MYC 转基因小鼠模型 MM，我们已经培育出一种新型转基因小鼠，Vk*MYChCRBN，表达完整的人类 CRBN (hCRBN) 基因受其内源性调控元件控制，使其对 IMiD 敏感。 正如之前对 Vk*MYC 模型所做的那样，我们将广泛描述新的 Vk*MYChCRBN 模型，并将用它来了解 IMiD 对肿瘤和免疫系统的影响 最终目标是为临床实践提供信息。

项目成果

Longitudinal single-cell analysis of a myeloma mouse model identifies subclonal molecular programs associated with progression.

• DOI: 10.1038/s41467-021-26598-w
• 发表时间: 2021-11-03
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Croucher DC;Richards LM;Tsofack SP;Waller D;Li Z;Wei EN;Huang XF;Chesi M;Bergsagel PL;Sebag M;Pugh TJ;Trudel S
• 通讯作者: Trudel S

Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression.

• DOI: 10.1038/s41467-018-07305-8
• 发表时间: 2018-12-03
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Calcinotto A;Brevi A;Chesi M;Ferrarese R;Garcia Perez L;Grioni M;Kumar S;Garbitt VM;Sharik ME;Henderson KJ;Tonon G;Tomura M;Miwa Y;Esplugues E;Flavell RA;Huber S;Canducci F;Rajkumar VS;Bergsagel PL;Bellone M
• 通讯作者: Bellone M

Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma.

• DOI: 10.1038/s41591-022-02178-3
• 发表时间: 2023-03
• 期刊: NATURE MEDICINE
• 影响因子: 82.9
• 作者: Larrayoz, Marta;Garcia-Barchino, Maria J.;Celay, Jon;Etxebeste, Amaia;Jimenez, Maddalen;Perez, Cristina;Ordonez, Raquel;Cobaleda, Cesar;Botta, Cirino;Fresquet, Vicente;Roa, Sergio;Goicoechea, Ibai;Maia, Catarina;Lasaga, Miren;Chesi, Marta;Bergsagel, P. Leif;Larrayoz, Maria J.;Calasanz, Maria J.;Campos-Sanchez, Elena;Martinez-Cano, Jorge;Panizo, Carlos;Rodriguez-Otero, Paula;Vicent, Silvestre;Roncador, Giovanna;Gonzalez, Patricia;Takahashi, Satoru;Katz, Samuel G.;Walensky, Loren D.;Ruppert, Shannon M.;Lasater, Elisabeth A.;Amann, Maria;Lozano, Teresa;Llopiz, Diana;Sarobe, Pablo;Lasarte, Juan J.;Planell, Nuria;Gomez-Cabrero, David;Kudryashova, Olga;Kurilovich, Anna;Revuelta, Maria V.;Cerchietti, Leandro;Agirre, Xabier;San Miguel, Jesus;Paiva, Bruno;Prosper, Felipe;Martinez-Climent, Jose A.
• 通讯作者: Martinez-Climent, Jose A.

Oncolytic immunotherapy and bortezomib synergy improves survival of refractory multiple myeloma in a preclinical model.

溶瘤免疫疗法和硼替佐米的协同作用可提高临床前模型中难治性多发性骨髓瘤的生存率。

• DOI: 10.1182/bloodadvances.2018025593
• 发表时间: 2019
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Thirukkumaran,ChandiniM;Shi,ZhongQiao;Nuovo,GerardJ;Luider,Joanne;Kopciuk,KarenA;Dong,Yuan;Mostafa,AhmedA;Thakur,Satbir;Gratton,Kathy;Yang,Ailian;Chin,AlexC;Coffey,MattC;Jimenez-Zepeda,VictorH;Stewart,Douglas;Chesi,Mar
• 通讯作者: Chesi,Mar