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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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Cyclooxygenase-2 Inhibition Induces Apoptosis Signaling via Death Receptors and Mitochondria in Hepatocellular Carcinoma..
M. A. Kern, A. M. Haugg, A. F. Koch, T. Schilling, K. Breuhahn, H. Walczak, B. Fleischer, C. Trautwein, C. Michalski, H. Schulze-Bergkamen, et al. (2006)
Cancer Res. 66, 7059-7066
   Abstract »    Full Text »    PDF »
Lack of {alpha}4 integrin expression in stem cells restricts competitive function and self-renewal activity.
G. V. Priestley, L. M. Scott, T. Ulyanova, and T. Papayannopoulou (2006)
Blood 107, 2959-2967
   Abstract »    Full Text »    PDF »
Herceptin Sensitizes ErbB2-Overexpressing Cells to Apoptosis by Reducing Antiapoptotic Mcl-1 Expression.
E. S. Henson, X. Hu, and S. B. Gibson (2006)
Clin. Cancer Res. 12, 845-853
   Abstract »    Full Text »    PDF »
Mcl-1 Is Essential for the Survival of Synovial Fibroblasts in Rheumatoid Arthritis.
H. Liu, P. Eksarko, V. Temkin, G. K. Haines III, H. Perlman, A. E. Koch, B. Thimmapaya, and R. M. Pope (2005)
J. Immunol. 175, 8337-8345
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Phase I and Pharmacokinetic Study of Flavopiridol followed by 1-{beta}-D-Arabinofuranosylcytosine and Mitoxantrone in Relapsed and Refractory Adult Acute Leukemias.
J. E. Karp, A. Passaniti, I. Gojo, S. Kaufmann, K. Bible, T. S. Garimella, J. Greer, J. Briel, B. D. Smith, S. D. Gore, et al. (2005)
Clin. Cancer Res. 11, 8403-8412
   Abstract »    Full Text »    PDF »
Apoptosis Induced by the Kinase Inhibitor BAY 43-9006 in Human Leukemia Cells Involves Down-regulation of Mcl-1 through Inhibition of Translation.
M. Rahmani, E. M. Davis, C. Bauer, P. Dent, and S. Grant (2005)
J. Biol. Chem. 280, 35217-35227
   Abstract »    Full Text »    PDF »
c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations.
H. Luo, Q. Li, J. O'Neal, F. Kreisel, M. M. Le Beau, and M. H. Tomasson (2005)
Blood 106, 2452-2461
   Abstract »    Full Text »    PDF »
BH3-only proteins in control: specificity regulates MCL-1 and BAK-mediated apoptosis.
C. Gelinas and E. White (2005)
Genes & Dev. 19, 1263-1268
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Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins.
S. N. Willis, L. Chen, G. Dewson, A. Wei, E. Naik, J. I. Fletcher, J. M. Adams, and D. C.S. Huang (2005)
Genes & Dev. 19, 1294-1305
   Abstract »    Full Text »    PDF »

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