The Journal of Experimental Medicine
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Published 17 February 2004. doi:10.1084/jem.20031858
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 4, 581-592
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Identification of a Cytokine-induced Antiapoptotic Molecule Anamorsin Essential for Definitive Hematopoiesis

Hirohiko Shibayama1, Emi Takai1, Itaru Matsumura1, Michiyoshi Kouno2, Eiichi Morii3, Yukihiko Kitamura3, Junji Takeda2, and Yuzuru Kanakura1

1 Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
2 Department of Social and Environmental Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
3 Department of Pathology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan

Address correspondence to Yuzuru Kanakura, Department of Hematology and Oncology, Osaka University Graduate School of Medicine, C9, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3871; Fax: 81-6-6879-3879; email: kanakura{at}bldon.med.osaka-u.ac.jp

Many growth factors and cytokines prevent apoptosis. Using an expression cloning method, we identified a novel antiapoptotic molecule named Anamorsin, which does not show any homology to known apoptosis regulatory molecules such as Bcl-2 family, caspase family, or signal transduction molecules. The expression of Anamorsin was completely dependent on stimulation with growth factors such as interleukin 3, stem cell factor, and thrombopoietin in factor-dependent hematopoietic cell lines, and forced expression of Anamorsin conferred resistance to apoptosis caused by growth factor deprivation in vitro. Furthermore, Anamorsin was found to act as an antiapoptotic molecule in vivo because Anamorsin-/- mice die in late gestation due to defective definitive hematopoiesis in the fetal liver (FL). Although the number of hematopoietic stem/progenitor cells in the FL did not decrease in these mice, myeloid, and particularly erythroid colony formation in response to cytokines, was severely disrupted. Also, Anamorsin-/- erythroid cells initiated apoptosis during terminal maturation. As for the mechanism of Anamorsin-mediated cell survival, a microarray analysis revealed that the expression of Bcl-xL and Jak2 was severely impaired in the FL of Anamorsin-/- mice. Thus, Anamorsin is considered to be a necessary molecule for hematopoiesis that mediates antiapoptotic effects of various cytokines.

Key Words: antiapoptosis • cytokine signal • expression cloning • definitive hematopoiesis • gene targeting

H. Shibayama and E. Takai contributed equally to this work.

The online version of this article contains supplemental material.

Abbreviations used in this paper: BFU-E, burst-forming unit-erythroid; EPO, erythropoietin; ES, embryonic stem; FL, fetal liver; IPTG, isopropyl-ß-D-thiogalactopyranoside; SCF, stem cell factor; STAT, signal transducer and activator of transcription; TPO, thrombopoietin.


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