Expression of inducible Bcl-X(S) in myeloid leukemia: compensatory upregulation of Bcl-X(L) 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. Bax 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.
Tacke
Frank
F
Department of Gastroenterology, Hepatology and Endocrinolog, Hannover Medical School, Hannover, Germany.
Marini
Frank C
FC
Zhao
Shourong
S
McQueen
Teresa
T
Konopleva
Marina
M
Ruvolo
Peter P
PP
Hu
Shi-Xue
SX
Xu
Hong-Ji
HJ
Andreeff
Michael
M
D000208:Acute Disease; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051020:bcl-X Protein
D000964:Antimetabolites, Antineoplastic; C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D003561:Cytarabine