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J Cell Biol. 2009 Nov 2;187(3):429-42. doi: 10.1083/jcb.200904049. Epub 2009 Oct 26.

MCL-1-dependent leukemia cells are more sensitive to chemotherapy than BCL-2-dependent counterparts.

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1
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02052, USA.

Abstract

Myeloid cell leukemia sequence 1 (MCL-1) and B cell leukemia/lymphoma 2 (BCL-2) are anti-apoptotic proteins in the BCL-2 protein family often expressed in cancer. To compare the function of MCL-1 and BCL-2 in maintaining cancer survival, we constructed complementary mouse leukemia models based on Emu-Myc expression in which either BCL-2 or MCL-1 are required for leukemia maintenance. We show that the principal anti-apoptotic mechanism of both BCL-2 and MCL-1 in these leukemias is to sequester pro-death BH3-only proteins rather than BAX and BAK. We find that the MCL-1-dependent leukemias are more sensitive to a wide range of chemotherapeutic agents acting by disparate mechanisms. In common across these varied treatments is that MCL-1 protein levels rapidly decrease in a proteosome-dependent fashion, whereas those of BCL-2 are stable. We demonstrate for the first time that two anti-apoptotic proteins can enable tumorigenesis equally well, but nonetheless differ in their influence on chemosensitivity.

PMID:
19948485
PMCID:
PMC2779245
DOI:
10.1083/jcb.200904049
[Indexed for MEDLINE]
Free PMC Article
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