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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4298-4307.
Prepublished online as a Blood First Edition Paper on February 15, 2005; DOI 10.1182/blood-2004-08-3372.
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Submitted August 31, 2004
Accepted January 21, 2005
Shared and distinct roles mediated through C-terminal subdomains of Acute Myeloid Leukemia/Runt-related transcription factor molecules in murine development
Yoko Fukushima-Nakase, Yoshinori Naoe, Ichiro Taniuchi, Hajime Hosoi, Tohru Sugimoto, and Tsukasa Okuda*
Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Kyoto, Japan; Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Kyoto, Japan
Laboratory for Transcriptional Regulation, Research Center for Allergy and Immunology, RIKEN (The Institute of Physical and Chemical Research), Yokohama, Kanagawa, Japan
Laboratory for Transcriptional Regulation, Research Center for Allergy and Immunology, RIKEN (The Institute of Physical and Chemical Research), Yokohama, Kanagawa, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Yokohama, Kanagawa, Japan
Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Kyoto, Japan
Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Kyoto, Japan
* Corresponding author; email: okuda{at}koto.kpu-m.ac.jp.
AML1/Runx1 is a frequent target of human leukemia-associated gene aberration, and encodes a transcription factor with non-redundant biologic functions in initial development of definitive hematopoiesis, T-cell development, and steady state platelet production. AML1/Runx1 and two closely related family genes, AML2/Runx3 and AML3/Runx2/Cbfa1, present in mammals, comprise the Runt-domain transcription factor family. Although they have similar structural and biochemical properties, gene-targeting experiments have identified distinct biologic roles. To directly determine the presence of functional overlap among Runx family molecules, we replaced the C-terminal portion of AML1 with that derived from its family members, which are variable in contrast to conserved Runt domain, using the gene knock-in method. We found that C-terminal portions of either AML2 or AML3 could functionally replace that of AML1 for myeloid development in culture and within the entire mouse. However, while AML2 substituted for AML1 could effectively rescue lymphoid lineages, AML3 could not, resulting in a smaller thymus and lymphoid deficiency in peripheral blood. Substitution by the C-terminal portion of AML3 also led to high infantile mortality and growth retardation, suggesting that AML1 has as yet unidentified effects on these phenotypes. Thus, the C-terminal portions of Runx family members have both similar and distinct biologic functions.
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