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Science 307 (5712): 1101-1104

Copyright © 2005 by the American Association for the Advancement of Science

Obligate Role of Anti-Apoptotic MCL-1 in the Survival of Hematopoietic Stem Cells

Joseph T. Opferman,1,2* Hiromi Iwasaki,2 Christy C. Ong,1,2 Heikyung Suh,1,2 Shin-ichi Mizuno,2 Koichi Akashi,2{dagger} Stanley J. Korsmeyer1,2{dagger}

Abstract: 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. We tested myeloid leukemia–1 (MCL-1) as an attractive candidate that is highly expressed in HSCs and regulated by growth factor signals. Inducible deletion of Mcl-1 in mice resulted in ablation of bone marrow. This resulted in the loss of early bone marrow progenitor populations, including HSCs. Moreover, growth factors including stem cell factor increased transcription of the Mcl-1 gene and required MCL-1 to augment survival of purified bone marrow progenitors. Deletion of Mcl-1 in other tissues, including liver, did not impair survival. Thus, MCL-1 is a critical and specific regulator essential for ensuring the homeostasis of early 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's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.

{dagger} 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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   Abstract »    Full Text »    PDF »
Glycogen Synthase Kinase 3{alpha} and 3{beta} Mediate a Glucose-Sensitive Antiapoptotic Signaling Pathway To Stabilize Mcl-1.
Y. Zhao, B. J. Altman, J. L. Coloff, C. E. Herman, S. R. Jacobs, H. L. Wieman, J. A. Wofford, L. N. Dimascio, O. Ilkayeva, A. Kelekar, et al. (2007)
Mol. Cell. Biol. 27, 4328-4339
   Abstract »    Full Text »    PDF »
Functional Linkage between NOXA and Bim in Mitochondrial Apoptotic Events.
J. Han, L. A. Goldstein, W. Hou, and H. Rabinowich (2007)
J. Biol. Chem. 282, 16223-16231
   Abstract »    Full Text »    PDF »
De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells.
Y. Tadokoro, H. Ema, M. Okano, E. Li, and H. Nakauchi (2007)
J. Exp. Med. 204, 715-722
   Abstract »    Full Text »    PDF »
Structural insights into the degradation of Mcl-1 induced by BH3 domains.
P. E. Czabotar, E. F. Lee, M. F. van Delft, C. L. Day, B. J. Smith, D. C. S. Huang, W. D. Fairlie, M. G. Hinds, and P. M. Colman (2007)
PNAS 104, 6217-6222
   Abstract »    Full Text »    PDF »
Targeting the mast cell: beyond KIT.
C. Akin (2007)
Blood 109, 2674-2675
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Mcl-1 Depletion in Apoptosis Elicited by Ionizing Radiation in Peritoneal Resident Macrophages of C3H Mice.
Y. Kubota, K. Kinoshita, K. Suetomi, A. Fujimori, and S. Takahashi (2007)
J. Immunol. 178, 2923-2931
   Abstract »    Full Text »    PDF »
The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages.
I. Dzhagalov, A. St. John, and Y.-W. He (2007)
Blood 109, 1620-1626
   Abstract »    Full Text »    PDF »
Commonly dysregulated genes in murine APL cells.
W. Yuan, J. E. Payton, M. S. Holt, D. C. Link, M. A. Watson, J. F. DiPersio, and T. J. Ley (2007)
Blood 109, 961-970
   Abstract »    Full Text »    PDF »
Anti-Apoptotic MCL-1 Plays a Critical Role in Maintenance of Normal and Malignant Human Hematopoietic Stem Cells through FLT3 Signaling..
G. Yoshimoto, T. Miyamoto, T. Iino, Y. Kikushige, H. Niiro, H. Iwasaki, M. Harada, and K. Akashi (2006)
Blood (ASH Annual Meeting Abstracts) 108, 11
   Abstract »    PDF »
The Protein Kinase C{delta} Catalytic Fragment Targets Mcl-1 for Degradation to Trigger Apoptosis.
L. A. Sitailo, S. S. Tibudan, and M. F. Denning (2006)
J. Biol. Chem. 281, 29703-29710
   Abstract »    Full Text »    PDF »
An Internal EELD Domain Facilitates Mitochondrial Targeting of Mcl-1 via a Tom70-dependent Pathway.
C.-H. Chou, R.-S. Lee, and H.-F. Yang-Yen (2006)
Mol. Biol. Cell 17, 3952-3963
   Abstract »    Full Text »    PDF »

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