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

Frank Tacke; Frank C. Marini; Shourong Zhao; Teresa McQueen; Marina Konopleva; Peter P. Ruvolo; Shi Xue Hu; Hong Ji Xu; Michael Andreeff

doi:10.4161/cbt.3.3.734

Expression of inducible Bcl-X_S in myeloid leukemia: Compensatory upregulation of Bcl-X_L and Bcl-2 prevents apoptosis and chemosensitization

Frank Tacke, Frank C. Marini, Shourong Zhao, Teresa McQueen, Marina Konopleva, Peter P. Ruvolo, Shi Xue Hu, Hong Ji Xu, Michael Andreeff

Leukemia

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	340-347
Number of pages	8
Journal	Cancer Biology and Therapy
Volume	3
Issue number	3
DOIs	https://doi.org/10.4161/cbt.3.3.734
State	Published - Mar 2004

Keywords

AML
Apoptosis
Bcl-2
Bcl-Xlong
Bcl-Xshort

ASJC Scopus subject areas

Molecular Medicine
Oncology
Pharmacology
Cancer Research

Access to Document

10.4161/cbt.3.3.734

Cite this

@article{ce1c55b8b613468eb0ab38d254a4fc8a,

title = "Expression of inducible Bcl-XS in myeloid leukemia: Compensatory upregulation of Bcl-XL and Bcl-2 prevents apoptosis and chemosensitization",

abstract = "Programmed cell death and survival are controlled by complex pathways, with the anti-apoptotic proteins Bcl-2 and Bcl-XL and the pro-apoptotic proteins Bax and Bcl-XS being major regulators. Variations in the expression of Bcl-XS have been observed in leukemic cells from acute myeloid leukemia (AML) patients and correlated with clinical outcome, but the impact of Bcl-XS on molecular pathophysiological mechanisms and the potential role of Bcl-XS as a therapeutic target in AML are not yet defined. In order to analyze the functional relevance of Bcl-XS in AML, Bcl-XS 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-XS 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-XL in MO7e and HL-60, and Bcl-2 in HL-60 cells resulting in increased protein levels. Bax levels were unchanged. Bcl-XL and Bcl-2 were found to heterodimerize with Bcl-XS, 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.",

keywords = "AML, Apoptosis, Bcl-2, Bcl-Xlong, Bcl-Xshort",

author = "Frank Tacke and Marini, {Frank C.} and Shourong Zhao and Teresa McQueen and Marina Konopleva and Ruvolo, {Peter P.} and Hu, {Shi Xue} and Xu, {Hong Ji} and Michael Andreeff",

year = "2004",

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doi = "10.4161/cbt.3.3.734",

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T1 - Expression of inducible Bcl-XS in myeloid leukemia

T2 - Compensatory upregulation of Bcl-XL and Bcl-2 prevents apoptosis and chemosensitization

AU - Tacke, Frank

AU - Marini, Frank C.

AU - Zhao, Shourong

AU - McQueen, Teresa

AU - Konopleva, Marina

AU - Ruvolo, Peter P.

AU - Hu, Shi Xue

AU - Xu, Hong Ji

AU - Andreeff, Michael

PY - 2004/3

Y1 - 2004/3

N2 - Programmed cell death and survival are controlled by complex pathways, with the anti-apoptotic proteins Bcl-2 and Bcl-XL and the pro-apoptotic proteins Bax and Bcl-XS being major regulators. Variations in the expression of Bcl-XS have been observed in leukemic cells from acute myeloid leukemia (AML) patients and correlated with clinical outcome, but the impact of Bcl-XS on molecular pathophysiological mechanisms and the potential role of Bcl-XS as a therapeutic target in AML are not yet defined. In order to analyze the functional relevance of Bcl-XS in AML, Bcl-XS 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-XS 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-XL in MO7e and HL-60, and Bcl-2 in HL-60 cells resulting in increased protein levels. Bax levels were unchanged. Bcl-XL and Bcl-2 were found to heterodimerize with Bcl-XS, 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.

AB - Programmed cell death and survival are controlled by complex pathways, with the anti-apoptotic proteins Bcl-2 and Bcl-XL and the pro-apoptotic proteins Bax and Bcl-XS being major regulators. Variations in the expression of Bcl-XS have been observed in leukemic cells from acute myeloid leukemia (AML) patients and correlated with clinical outcome, but the impact of Bcl-XS on molecular pathophysiological mechanisms and the potential role of Bcl-XS as a therapeutic target in AML are not yet defined. In order to analyze the functional relevance of Bcl-XS in AML, Bcl-XS 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-XS 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-XL in MO7e and HL-60, and Bcl-2 in HL-60 cells resulting in increased protein levels. Bax levels were unchanged. Bcl-XL and Bcl-2 were found to heterodimerize with Bcl-XS, 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.

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