herboxidiene and Leukemia--Myeloid--Acute

Splice modulators have been assessed clinically in treating haematologic malignancies exhibiting splice factor mutations and acute myeloid leukaemia. However, the mechanisms by which such modulators repress leukaemia remain to be elucidated.. The primary goal of this assessment was to assess the molecular mechanism by which the natural splice modulator GEX1A kills leukaemic cells in vitro and within in vivo mouse models.. Using human leukaemic cell lines, we assessed the overall sensitivity these cells have to GEX1A via EC. We found that, in vitro, GEX1A induced an MCL-1 isoform shift to pro-apoptotic MCL-1S in all leukaemic cell types, though sensitivity to GEX1A-induced apoptosis was negatively associated with BCL-xL expression. In BCL-2-expressing leukaemic cells, GEX1A induced BCL-2-dependent apoptosis by converting pro-survival BCL-2 into a cell killer. Thus, GEX1A + selective BCL-xL inhibition induced synergism in killing leukaemic cells, while GEX1A + BCL-2 inhibition showed antagonism in BCL-2-expressing leukaemic cells. In addition, GEX1A sensitised FLT3-ITD. Our study suggests that GEX1A is a potent anti-leukaemic agent in combination with BCL-xL inhibitors, which targets leukaemic blasts and leukaemia stem cells through distinct mechanisms.

Topics: Animals; Apoptosis; bcl-X Protein; Cell Line, Tumor; Fatty Alcohols; Humans; Leukemia, Myeloid, Acute; Mice; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-bcl-2; Pyrans