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Blood, 15 September 2004, Vol. 104, No. 6, pp. 1816-1824.
Prepublished online as a Blood First Edition Paper on May 25, 2004; DOI 10.1182/blood-2004-01-0395.
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Submitted February 2, 2004
Accepted April 22, 2004
Cholesterol Synthesis and Import Contribute to Protective Cholesterol Increments in Acute Myeloid Leukemia Cells
Deborah E Banker*, Sasha J Mayer, Henry Y Li, Cheryl L Willman, Frederick R Appelbaum, and Richard A Zager
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Pathology and Medicine, University of New Mexico Cancer Research Facility, Albuquerque, NM, USA
* Corresponding author; email: dbanker{at}fhcrc.org.
Cholesterol levels are abnormally increased in many acute myeloid leukemia (AML) samples exposed in vitro to chemotherapy. Blocking these acute cholesterol responses selectively sensitizes AML cells to therapeutics. Thus, defining the molecular mechanism(s) by which AMLs accomplish these protective cholesterol increments might elucidate novel therapeutic targets. We now report that the levels of messenger RNAs encoding the cholesterol synthesis-regulating enzyme, 3-hydroxy-3-methylglutaryl coenzyme-A reductase, and the cholesterol-importing low-density lipoprotein (LDL) receptor were both increased by daunorubicin (DNR) and/or cytarabine (ARA-C) treatments in almost three-quarters of cultured AML samples. However, less than one-third of AMLs significantly increased LDL accumulation during drug treatments, suggesting that de novo synthesis is the primary mechanism by which most AMLs increase cholesterol levels during drug exposures. LDL increments were not correlated with cholesterol increments in ARA-C-treated AMLs. However, LDL and cholesterol increments did correlate in DNR-treated AMLs where they were measured, suggesting that a subset of AMLs may rely upon increased LDL accumulation during treatment with particular drugs. Our data suggest that cholesterol synthesis inhibitors may improve the efficacy of standard anti-leukemia regimens, but that for maximum benefit, therapy may need to be tailored for individual leukemia patients.
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