Role of Bim in mediating CAM-DR in hematopoietic tumors

描述（由申请方提供）：未能消除微小残留病（MRD）继续限制化疗在多发性骨髓瘤（MM）、急性髓性白血病（AML）和慢性髓性白血病（CML）中的成功。我们提出肿瘤微环境由专门的小生境组成，这些小生境有助于新生耐药，并最终导致造血系统肿瘤无法消除最小（MRD）。与造血肿瘤特别相关的一个微环境是骨髓。骨髓微环境支持细胞因子、生长因子和细胞外基质组分的高局部浓度。我们以前的研究表明，通过β 1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凋亡。我们将这种表型称为细胞粘附介导的耐药性或CAM-DR。本提案将研究Bim在介导CAM-DR表型中的作用。此外，该提案将描绘导致粘附细胞中Bim水平降低的途径和靶点。最后，我们将确定靶向β 1整合素介导的信号传导是否增加了化疗在骨髓基质和耐药性SCID-Hu模型中的疗效。为此，该补助金的具体目标1将确定降低Bim水平在介导CAM-DR表型中的总体贡献。本基金的具体目标2将确定Bim的翻译后调节是否与粘附细胞中Bim水平降低有因果关系。在本提案的具体目标3中，我们将破坏β 1整联蛋白介导的信号传导，并确定这是否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性药物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：未能消除与造血系统肿瘤相关的微小残留病变阻碍了标准化疗的成功。在这个提议中，我们将测试是否破坏β 1整合素介导的信号增加标准化疗在骨髓微环境中的效力。

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.