Expression of NPM-RARalpha fusion gene in hematopoietic cells confers sensitivity to troglitazone-induced apoptosis.
We have investigated the effects of acute promyelocytic leukemia (APL) fusion gene NPM-RARalpha on the function of PPARgamma using the monoblastic cell line U937. U937 cells were transduced using a retrovirus carrying NPM-RARalpha. While treatment with the synthetic PPARgamma ligand troglitazone (TG) had no effect on the viability of U937 cells, TG treatment of U937/NPM-RARalpha cells resulted in a dramatic decrease in cell viability, dependent upon both the concentration of TG and the level of expression of NPM-RARalpha. Analysis of the cell cycle profile and flow cytometry with annexin V confirmed that these effects of TG were due to induction of apoptosis. Induction of apoptosis was accompanied by caspase-8 and caspase-9 activation, and could be blocked by treatment with the caspase inhibitor Z-VAD-FMK. Cotreatment of U937/NPM-RARalpha cells with all-trans retinoic acid (atRA) abrogated the induction of apoptosis by TG. Induction of apoptosis was seen also in the PML-RARalpha-expressing APL cell line NB4, and in several other atRA-sensitive leukemia cell lines, demonstrating that this effect is limited neither to the monocyte lineage nor to the rare NPM-RARalpha fusion variant. RXRalpha/NPM-RARalpha heterodimers were found to interact directly with a PPARgamma-responsive element in vitro. We conclude that in the presence of X-RARalpha, TG induces cell death due to apoptosis via the caspase pathway. These observations suggest the investigation of PPARgamma ligands as therapeutic agents in acute leukemia.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000187:drug effects; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects; D000077288:Troglitazone; D020298:U937 Cells
D000970:Antineoplastic Agents; D002839:Chromans; C120276:NPM-RARalpha protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D020169:Caspases; D000077288:Troglitazone