Role of Bim in mediating CAM-DR in hematopoietic tumors

Bim 在介导造血肿瘤 CAM-DR 中的作用

• 批准号: 7482486
• 负责人: Lori A Hazlehurst
• 金额: $ 28.39万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-08 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7482486
• 关键词: Acute Myelocytic Leukemia; Adhesions; Apoptosis; Binding; Biological Models; Bone Marrow; Cell Adhesion; Cell Death; Cell Survival; Cells; Cessation of life; Chronic Myeloid Leukemia; Clinical; Coculture Techniques; Cultured Cells; Data; Disruption; Doctor of Philosophy; Drug resistance; Engraftment; Event; Extracellular Matrix; Failure; Fibronectins; Goals; Grant; Growth Factor; Hematopoietic Neoplasms; Homing; Human; In Vitro; Integrins; MSX1 gene; Mediating; Melphalan; Modeling; Multi-Drug Resistance; Multiple Myeloma; Myeloid Leukemia; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Phosphorylation; Post-Translational Regulation; Regulation; Relative (related person); Research Personnel; Residual Neoplasm; Resistance; Role; Signal Transduction; Small Interfering RNA; Specimen; Standards of Weights and Measures; Suspension substance; Suspensions; Testing; Work; bone; chemotherapy; cytokine; cytotoxic; drug efficacy; in vivo Model; integrin-linked kinase; killings; leukemia; loris; neoplastic cell; prevent; programs; response; small hairpin RNA; src-Family Kinases; success; tool; trafficking; tumor; vector

DESCRIPTION (provided by applicant): Failure to eliminate minimal residual disease (MRD) continues to limit the success of chemotherapy in multiple myeloma (MM), acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). We propose the tumor microenvironment consists of specialized niches that contribute to de-novo resistance and ultimately to the failure to eliminate minimal (MRD) in hematopoietic tumors. One microenvironment that is particularly relevant to hematopoietic tumors is the bone marrow. The bone marrow microenvironment supports high local concentrations of cytokines, growth factors and components of extracellular matrixes. We previously showed that cell adhesion via beta 1 integrins to FN is sufficient to protect leukemic and MM cells from drug-induced apoptosis. We have referred to this phenotype as cell adhesion mediated drug resistance or CAM-DR. This proposal will investigate the role of Bim in mediating the CAM-DR phenotype. In addition, this proposal will delineate pathways and targets that are causative for reduced Bim levels in adhered cells. Finally, we will determine whether targeting beta 1 integrin mediated signaling increases the efficacy of chemotherapy in a bone marrow stroma and SCID-Hu model of drug resistance. To this end specific aim 1 of this grant will determine the overall contribution of reduced Bim levels in mediating the CAM-DR phenotype. Specific aim 2 of this grant will determine whether post-translational regulation of Bim is causally related to reduced Bim levels in adherent cells. In specific aim 3 of this proposal we will disrupt beta 1 integrin mediated signaling and determine whether this results in increased cell death induced by chemotherapy in a bone marrow stroma co-culture model and the SCID-Hu in vivo model. In summary, we hypothesize that cell adhesion mediated reduction in Bim levels is a critical determinant of CAM-DR and contributes to the failure of currently used cytotoxics to eliminate MRD in hematopoietic tumors. This hypothesis will be rigorously tested in this proposal. Relevance: The failure to eliminate minimal residual disease associated with hematopoietic tumors impedes the success of standard chemotherapy. In this proposal we will test whether disrupting beta 1 integrin mediated signaling increases the potency of standard chemotherapy in the bone marrow microenvironment.

描述（由申请人提供）：未能消除微小残留病（MRD）继续限制多发性骨髓瘤（MM）、急性髓性白血病（AML）和慢性粒细胞性白血病（CML）化疗的成功。我们提出，肿瘤微环境由特殊的生态位组成，这些生态位有助于从头产生耐药性，并最终导致无法消除造血肿瘤中的微小耐药（MRD）。与造血肿瘤特别相关的一种微环境是骨髓。骨髓微环境支持局部高浓度的细胞因子、生长因子和细胞外基质成分。我们之前表明，通过 β1 整合素与 FN 的细胞粘附足以保护白血病和 MM 细胞免受药物诱导的细胞凋亡。我们将这种表型称为细胞粘附介导的耐药性或 CAM-DR。该提案将研究 Bim 在介导 CAM-DR 表型中的作用。此外，该提案将描述导致粘附细胞中 Bim 水平降低的途径和目标。最后，我们将确定靶向 β1 整合素介导的信号传导是否会增加骨髓基质和 SCID-Hu 耐药模型中化疗的疗效。为此，本次拨款的具体目标 1 将确定降低的 Bim 水平在调节 CAM-DR 表型中的总体贡献。该资助的具体目标 2 将确定 Bim 的翻译后调节是否与贴壁细胞中 Bim 水平降低存在因果关系。在该提案的具体目标 3 中，我们将破坏 β1 整合素介导的信号传导，并确定这是否会导致骨髓基质共培养模型和 SCID-Hu 体内模型中化疗诱导的细胞死亡增加。总之，我们假设细胞粘附介导的 Bim 水平降低是 CAM-DR 的关键决定因素，并导致目前使用的细胞毒素无法消除造血肿瘤中的 MRD。这一假设将在本提案中得到严格检验。相关性：未能消除与造血肿瘤相关的微小残留病阻碍了标准化疗的成功。在本提案中，我们将测试破坏 β1 整合素介导的信号传导是否会增加骨髓微环境中标准化疗的效力。