Stromal interactions reduce apoptotic priming and increase drug resistance in CLL.
Major finding: Stromal interactions reduce apoptotic priming and increase drug resistance in CLL.
Clinical relevance: PI3Kδ inhibitors decrease stromal interactions and increase CLL cell priming.
Impact: BH3 profiling may be used to identify patients with CLL who are likely to respond to chemotherapy.
Chronic lymphocytic leukemia (CLL) is treatable with conventional chemotherapy, but ultimately reoccurs. Residual CLL cells in the lymph nodes or bone marrow are thought to receive survival and proliferation cues that contribute to chemoresistance. Davids and colleagues hypothesized that these stromal interactions may affect whether CLL cells are primed to undergo apoptosis. Through the use of BH3 profiling, in which mitochondrial permeabilization is measured in response to treatment with prodeath BH3 peptides to assess how close cells are to the apoptotic threshold, the authors found that higher levels of apoptotic priming in CLL cells were associated with response to chemotherapy and that coculture of CLL cells with stromal cells decreased apoptotic priming and increased drug resistance. Consistent with a model in which the stroma protects CLL cells by decreasing apoptotic priming, circulating CLL cells isolated from the peripheral blood of patients were significantly more primed than CLL cells derived from the bone marrow. Mobilization of CLL cells away from the stroma may therefore increase the effectiveness of CLL therapy. Intriguingly, CAL-101, a phosphoinositide 3-kinase isoform p110δ (PI3Kδ) inhibitor with clinical activity in CLL, causes a transient increase in the number of lymphocytes in the blood, suggesting that this drug may induce a release of sequestered CLL cells. Indeed, CAL-101 significantly decreased cell adhesion in CLL cells cocultured with stromal cells, which was associated with restored drug sensitivity, and significantly increased apoptotic priming. Although further research is needed to determine the mechanism by which stromal cells affect mitochondrial priming of CLL cells, these findings suggest that BH3 profiling may be a predictor of clinical responses in CLL and that combined use of drugs that target stromal interactions may potentiate the effects of conventional CLL therapy.