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Molecular and Cellular Biology, December 2004, p. 10814-10825, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10814-10825.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Leukemogenesis Caused by Incapacitated GATA-1 Function

Ritsuko Shimizu,1,2 Takashi Kuroha,1 Osamu Ohneda,1,2 Xiaoqing Pan,1,2 Kinuko Ohneda,1,2 Satoru Takahashi,1 Sjaak Philipsen,3 and Masayuki Yamamoto1,2*

Graduate School of Comprehensive Human Sciences, Center for Tsukuba Advanced Research Alliance,1 ERATO Environmental Response Project, University of Tsukuba, Tsukuba, Japan,2 Department of Cell Biology, Medical Genetics Cluster, Erasmus MC, Rotterdam, The Netherlands3

Received 28 August 2004/ Accepted 27 September 2004

GATA-1 is essential for the development of erythroid and megakaryocytic lineages. We found that GATA-1 gene knockdown female (GATA-1.05/X) mice frequently develop a hematopoietic disorder resembling myelodysplastic syndrome that is characterized by the accumulation of progenitors expressing low levels of GATA-1. In this study, we demonstrate that GATA-1.05/X mice suffer from two distinct types of acute leukemia, an early-onset c-Kit-positive nonlymphoid leukemia and a late-onset B-lymphocytic leukemia. Since GATA-1 is an X chromosome gene, two types of hematopoietic cells reside within heterozygous GATA-1 knockdown mice, bearing either an active wild-type GATA-1 allele or an active mutant GATA-1.05 allele. In the hematopoietic progenitors with the latter allele, low-level GATA-1 expression is sufficient to support survival and proliferation but not differentiation, leading to the accumulation of progenitors that are easily targeted by oncogenic stimuli. Since such leukemia has not been observed in GATA-1-null/X mutant mice, we conclude that the residual GATA-1 activity in the knockdown mice contributes to the development of the malignancy. This de novo model recapitulates the acute crisis found in preleukemic conditions in humans.

* Corresponding author. Mailing address: Center for TARA, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan. Phone: 81-298-53-6158. Fax: 81-298-53-7318. E-mail: masi{at}tara.tsukuba.ac.jp.

Molecular and Cellular Biology, December 2004, p. 10814-10825, Vol. 24, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.24.10814-10825.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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