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Obligate Role of Anti-Apoptotic MCL-1 in the Survival of Hematopoietic Stem Cells
Joseph T. Opferman,1,2*Hiromi Iwasaki,2Christy C. Ong,1,2Heikyung Suh,1,2Shin-ichi Mizuno,2Koichi Akashi,2Stanley J. Korsmeyer1,2
Apoptosis is important in controlling hematopoietic stem cell(HSC) numbers. However, the specific BCL-2 family member(s)that regulate HSC homeostasis are not precisely defined. Wetested myeloid leukemia–1 (MCL-1) as an attractive candidatethat is highly expressed in HSCs and regulated by growth factorsignals. Inducible deletion of Mcl-1 in mice resulted in ablationof bone marrow. This resulted in the loss of early bone marrowprogenitor populations, including HSCs. Moreover, growth factorsincluding stem cell factor increased transcription of the Mcl-1gene and required MCL-1 to augment survival of purified bonemarrow progenitors. Deletion of Mcl-1 in other tissues, includingliver, did not impair survival. Thus, MCL-1 is a critical andspecific regulator essential for ensuring the homeostasis ofearly hematopoietic progenitors.
1 Howard Hughes Medical Institute, Department of Cancer Immunology and AIDS, Pathology and Medicine, Harvard Medical School, Boston, MA 02115, USA. 2 Dana Farber Cancer Institute, Department of Cancer Immunology and AIDS, Pathology and Medicine, Harvard Medical School, Boston, MA 02115, USA.
* Present address: Department of Biochemistry, St. Jude Children'sResearch Hospital, 332 North Lauderdale, Memphis, TN 38105,USA.
To whom correspondence should be addressed. E-mail: Koichi_Akashi{at}dfci.harvard.edu (K.A.); Stanley_Korsmeyer{at}dfci.harvard.edu (S.K.)
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