Expression of inducible bcl-XS in myeloid leukemia -: Compensatory Upregulation of Bcl-XL and bcl-2 prevents apoptosis and chemosensitization

Programmed cell death and survival are controlled by complex pathways, with the anti-apoptotic proteins Bcl-2 and Bcl-X-L and the pro-apoptotic proteins Bax and Bcl-X-S being major regulators. Variations in the expression of Bcl-X-S have been observed in leukemic cells from acute myeloid leukemia (AML) patients and correlated with clinical outcome, but the impact of Bcl-X-S on molecular pathophysiological mechanisms and the potential role of Bcl-X-S as a therapeutic target in AML are not yet defined. In order to analyze the functional relevance of Bcl-X-S in AML, Bcl-X-S was moderately (2-3 fold) overexpressed in the AML cell lines HL-60 and MO7e by transfection with a tetracycline-regulatable Bcl-X-S expression system. Increased Bcl-X-S did not change the rate of spontaneous apoptosis, chemosensitivity to ara-C, or cell cycle kinetics. Further analysis of this unexpected result revealed a compensatory transcriptional upregulation of endogenous anti-apoptotic Bcl-X-L in MO7e and HL-60, and Bcl-2 in HL-60 cells resulting in increased protein levels. Box levels were unchanged. Bcl-X-L and Bcl-2 were found to heterodimerize with Bcl-X-S, thereby providing a possible explanation for the abrogation of its pro-apoptotic function. These results suggest the existence of a regulatory mechanism aimed to protect leukemic cells from pro-apoptotic stimuli.