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Chemotherapy and the bone marrow stroma

In this issue of Leukemia and Lymphoma, using an in vitro coculture approach Moshaver et al. explore the mechanisms whereby bone marrow stromal cells (BMSCs) protect leukemia from chemotherapyinduced apoptosis [1]. They also examine how this stromal supportive ability may itself be affected by chemotherapy. Their results suggest that coculture of the HL-60 leukemia cell line with HS-5 fibroblasts or primary BMSCs following HL-60 pre-treatment with cytarabine preserves leukemic proliferation and reduces chemotherapy-induced apoptosis. This effect appears to be mediated via both soluble factors and cell – cell contact and is significantly decreased upon exposure of BMSCs to cytarabine. In addition, the authors demonstrate that coculture of BMSCs with untreated primary AML cells decreases rates of spontaneous apoptosis in patient samples, and this effect was significantly lessened when BMSCs were pre-treated with cytarabine. Taken together, these data highlight the potential role of the bone marrow microenvironment in leukemia resistance to chemotherapy and the perpetuation of minimal residual disease. While many studies have previously shown that BMSC coculture promotes leukemia cell viability, few have specifically examined the protective effect of stromal cells against chemotherapy-induced leukemia apoptosis. Yet the limited number of reports have yielded consistent evidence that bone marrow stroma affects chemotherapeutic efficacy in vitro. In a study of ALL cell lines cocultured with BMSCs, Mudry et al. found that coculture supported leukemic cell proliferation and decreased chemotherapyinduced apoptosis [2]. This protective effect was, however, substantially dependent on cell contact and could be significantly blocked by stromal VCAM-1 inhibition. Nefedova et al. demonstrated that primary BMSCs in coculture with myeloma cell lines protected myeloma from drug-induced apoptosis [3]. Conditioned media harvested from BMSC cultures did not have an anti-apoptotic effect, implying that cell – cell contact was required. Interestingly, the authors subsequently demonstrated that conditioned media harvested from BMSC-myeloma cocultures was protective, suggesting that reciprocal interactions between BMSC and myeloma cells were necessary to yield soluble antiapoptotic factors. In the current study, the authors expand their work to investigate the impact of chemotherapy on the bone marrow (BM) stroma itself vis-à-vis its ability to provide a chemo-protective environment for leukemia. This is a logical extension of previous studies and also harkens to the known impact of chemotherapeutics and radiotherapeutics on the BM microenvironment. It has long been clear from morphologic analyses that chemotherapy and radiation can significantly alter the bone marrow stroma, with high intensity therapies leading to stromal degeneration. The specific molecular signaling events that occur following sublethal damage to the stroma, and the diverse ramifications of these stromal responses, however, remain to be fully characterized. Perhaps the most extensive work involving the effect of chemoradiotherapeutics on the BM stromal microenvironment has been performed with respect to hematopoietic stem cell transplantation and benign hematopoiesis. Using a NOD/SCID stem cell transplant mouse model, Ponomaryov et al. demonstrated that BM stromal cell production of the chemokine SDF-1 was upregulated in response to