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

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish
Pages (from-to)340-347
Number of pages8
JournalCancer Biology and Therapy
Volume3
Issue number3
DOIs
StatePublished - Mar 2004
Externally publishedYes

Keywords

  • AML
  • Apoptosis
  • Bcl-2
  • Bcl-Xlong
  • Bcl-Xshort

Fingerprint

Dive into the research topics of 'Expression of inducible Bcl-XS in myeloid leukemia: Compensatory upregulation of Bcl-XL and Bcl-2 prevents apoptosis and chemosensitization'. Together they form a unique fingerprint.

Cite this