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 Ruvolo, Shi Xue Hu, Hong Ji Xu, Michael Andreeff

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)340-347
Number of pages8
JournalCancer Biology and Therapy
Volume3
Issue number3
DOIs
StatePublished - Jan 1 2004

Fingerprint

Myeloid Leukemia
Acute Myeloid Leukemia
Up-Regulation
Apoptosis
Apoptosis Regulatory Proteins
HL-60 Cells
Cytarabine
Myeloid Cells
Tetracycline
Transfection
Cell Survival
Cell Cycle
Cell Death
Cell Line
Proteins
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Expression of inducible Bcl-X S in myeloid leukemia : Compensatory upregulation of Bcl-X L and Bcl-2 prevents apoptosis and chemosensitization. / Tacke, Frank; Marini, Frank C.; Zhao, Shourong; McQueen, Teresa; Konopleva, Marina; Ruvolo, Peter; Hu, Shi Xue; Xu, Hong Ji; Andreeff, Michael.

In: Cancer Biology and Therapy, Vol. 3, No. 3, 01.01.2004, p. 340-347.

Research output: Contribution to journalArticle

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