Overexpression of anti-apoptotic protein BCL-2 and hypermethylation are hallmarks of acute lymphoblastic leukemia (ALL) and can be pharmacologically addressed by venetoclax (VEN) and hypomethylating agents (HMA) such as azacytidine (AZA) or decitabine (DEC). Combined VEN and HMA application was recently successfully implemented into the clinical treatment regimen of acute myeloid leukemia but has so far not been investigated in ALL. We therefore analyzed the anti-leukemic potential of VEN+HMA in four ALL cell lines and identified potential modes of synergy to overcome mono-drug-induced resistance. All substances influenced cell proliferation and induced apoptosis in a subset of the tested cell lines. Investigating potential ways of synergy, combined VEN and HMA application resulted in significantly reduced metabolic activity in all investigated cell lines. In contrast, no synergistic effects were observed regarding the BCL-2 protein and methyltransferase expression or global methylation. Single cell RNAseq of a patient-derived xenograft model revealed that VEN interferes with both main energy supply routes, oxidative phosphorylation as well as glycolysis, to impede the cells' metabolism and mitochondrial activity. The addition of HMA, especially DEC, further increased anti-metabolic effects, leading to a strong reduction of basal and maximal respiration, ATP production and proton leakage. AZA-induced metabolic suppression as well as overall anti-leukemic activity alone and in combination with VEN was generally weaker compared to DEC. Altogether, we herein demonstrate that combined VEN and HMA application acts synergistically and significantly reduces the leukemic burden in ALL cell lines via impairment of tumor cell metabolism and mitochondrial function.
Maass et al. (Mon,) studied this question.