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Published online
doi:10.1083/jcb.200904049
The Journal of Cell Biology, Vol. 187, No. 3, 429-442
The Rockefeller University Press, 0021-9525 $30.00
© Brunelle et al.
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Article

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



Joslyn K. Brunelle1, Jeremy Ryan1, Derek Yecies1, Joseph T. Opferman2, and Anthony Letai1

1 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02052
2 Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, TN 38105

Correspondence to Anthony Letai: Anthony_Letai{at}dfci.harvard.edu

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 Eµ-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.

Abbreviations used in this paper: BCL-2, B cell leukemia/lymphoma 2; BH, BCL-2 homology; MCL-1, myeloid cell leukemia sequence 1.

© 2009 Brunelle et al.
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