Bone marrow stromal cells enhance the survival of chronic lymphocytic leukemia cells by regulating HES-1 gene expression and H3K27me3 demethylation.

Abstract

The majority of patients with chronic lymphocytic leukemia (CLL) are not cured by traditional chemotherapy. One possible explanation for this is that the microenvironment protects CLL cells from both spontaneous- and cytotoxic-mediated apoptosis. The present study was designed to investigate the mechanisms accounting for these effects, since this information is crucial to understanding CLL physiopathology and identifying potential treatment targets. The CLL cell line L1210 and primary CLL cells were cultured under different conditions: With serum, cyclophosphamide (CTX), or with monolayers and conditioned medium (CM) from the stromal cell line HESS-5. Apoptosis, Hes family BHLH transcription factor 1 (HES-1) gene and protein expression, and histone H3K27me3 DNA demethylation were determined. Co-culture of L1210 cells with HESS-5 cells significantly inhibited serum deprivation- and CTX-induced apoptosis of leukemia cells, and resulted in a significant increase in short-term proliferation. Soluble factors in the CM from HESS-5 cells had a negligible effect. The HESS-5 cell-mediated inhibition of apoptosis of CLL cells was associated with increased HES-1 expression and hypomethylation of the H3K27me3 gene in the leukemia cells. These results indicate that stromal cells enhance the survival of CLL cells by regulating the HES-1 gene and protein expression, as well as H3K27me3 DNA demethylation, and suggest that specific interactions between stromal and leukemia cells may enhance the resistance of leukemia cells to chemotherapy.