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

Abstract

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.

Importance of Crosstalk Between Chronic Lymphocytic Leukemia Cells and the Stromal Microenvironment: Direct Contact, Soluble Factors, and Extracellular Vesicles

“…Other authors highlight the possible epigenetic modifications induced by stromal cells. Xu et al observed that CLL B cell protection in the presence of the murine stromal cell line HESS-5 is associated with hypomethylation of the trimethylation of lysine 27 on histone H3 protein subunit (H3K27me3) ( 101 ). Coculture with different stromal cell lines showed increased oxidative phosphorylation in CLL, which probably helps to increase their metabolism, allowing these cells to meet the energy demands for transcription and translation ( 102 ).…”

Bone Marrow Lymphoid Niche Adaptation to Mature B Cell Neoplasms

“…The mutual activation of stromal cells and tumor cells also depends on the CLL-mediated activation of Notch2 in BM stromal cells, leading to C1q overexpression the reciprocal activation of the canonical Wnt pathway in CLL cells ( 84 ) Moreover, BM stromal cell derived CXCL12 exhibits a pro-survival effect on CLL tumor cells ( 44 , 85 , 86 ). BM Stromal cells may also induce protective epigenetic modifications in CLL B cells including hypomethylation of the lysine 27 of histone H3 protein subunit (H3K27me3) ( 87 ). Finally, BM stromal cells have an important role on CLL metabolism.…”