Role of Bim in mediating CAM-DR in hematopoietic tumors

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)、急性髓细胞白血病(AML)和慢性粒细胞白血病(CML)的化疗成功。我们认为，肿瘤微环境由特殊的小生境组成，这些小生境有助于去新生抵抗，并最终导致未能消除造血肿瘤中的最小(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。我们之前已经证明，通过β1整合素与FN的细胞黏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黏附介导的耐药或CAM-DR。这项建议将研究Bim在调节CAM-DR表型中的作用。此外，该提案将描述导致贴壁细胞中Bim水平降低的途径和靶点。最后，我们将确定靶向β1整合素介导的信号是否在骨髓基质和SCID-Hu耐药模型中增加化疗的疗效。为此，这笔赠款的具体目标1将确定降低的Bim水平在调节CAM-DR表型方面的总体贡献。这项资助的具体目标2将确定BIM的翻译后调节是否与贴壁细胞中BIM水平的降低有因果关系。在本提案的具体目标3中，我们将干扰β1整合素介导的信号转导，并在骨髓基质共培养模型和SCID-Hu体内模型中确定这是否会导致化疗诱导的细胞死亡增加。综上所述，我们假设细胞黏附介导的Bim水平的降低是CAM-DR的关键决定因素，并导致目前使用的细胞毒药物未能消除造血肿瘤中的MRD。这一假设将在这一提议中得到严格检验。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。在这项提案中，我们将测试干扰β1整合素介导的信号传递是否会增加骨髓微环境中标准化疗的效力。

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.