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Chronic myeloid leukemia (CML) is initially driven by the bcr-abl fusion oncoprotein. The identification of bcr-abl led to the discovery and rapid translation into the clinic of bcr-abl kinase inhibitors. Although, bcr-abl inhibitors are efficacious, experimental evidence indicates that targeting bcr-abl is not sufficient for elimination of minimal residual(More)
Imatinib mesylate is a potent, molecularly targeted therapy against the oncogenic tyrosine kinase BCR-ABL. Although imatinib mesylate has considerable efficacy against chronic myeloid leukemia (CML), advanced-stage CML patients frequently become refractory to this agent. The bone marrow is the predominant microenvironment of CML and is a rich source of both(More)
In this study, we show that conditioned media (CM) generated from bone marrow (BM)-derived mesenchymal stromal cells lead to BCR-ABL independent STAT3 activation. Activation of STAT3 is important not only for survival of CML cells but also for its protection against Nilotinib (NI), within the BM microenvironment. Reducing the expression of both JAK2 and(More)
Integrin-mediated adhesion influences cell survival and may prevent programmed cell death. Little is known about how drug-sensitive tumor cell lines survive initial exposures to cytotoxic drugs and eventually select for drug-resistant populations. Factors that allow for cell survival following acute cytotoxic drug exposure may differ from drug resistance(More)
The bone marrow microenvironment facilitates the survival, differentiation, and proliferation of hematopoietic cells. These cells are supported by fibroblast-like bone marrow stromal cells, osteoblasts, and osteoclasts which secrete soluble factors and extracellular matrix proteins that mediate these functions. This rich environment serves as a safe haven(More)
The bone marrow microenvironmental components interleukin (IL)-6 and fibronectin (FN) individually influence the proliferation and survival of multiple myeloma (MM) cells; however, in vivo, these effectors most likely work together. We examined signaling events, cell cycle progression, and levels of drug response in MM cells either adhered to FN via beta1(More)
Despite the success of tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML), minimal residual disease persists, requiring indefinite treatment. Accumulated evidence has shown that leukemic stem cells (LSCs) in the bone marrow can survive TKI treatment via downstream BCR-ABL1-independent signaling pathways that are(More)
Cancer cell adhesion confers a transient, de novo drug-resistant phenotype referred to as cell adhesion-mediated drug resistance (CAM-DR). In this report, we extend the CAM-DR phenotype to primary specimens from patients with myeloma, providing further evidence that CAM-DR is a viable clinical form of drug resistance. To examine mechanisms of cellular(More)
Accurate preclinical predictions of the clinical efficacy of experimental cancer drugs are highly desired but often haphazard. Such predictions might be improved by incorporating elements of the tumor microenvironment in preclinical models by providing a more physiological setting. In generating improved xenograft models, it is generally accepted that the(More)
The tumor cell environment may influence drug response through interactions with the extracellular matrix (ECM). We recently reported that adhesion of myeloma cells to fibronectin (FN) via beta1 integrins is associated with a cell adhesion mediated drug resistance (CAM-DR). Activation of beta1 integrins is known to influence both apoptosis and cell growth.(More)