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.
