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J. Biol. Chem., Vol. 279, Issue 4, 2873-2884, January 23, 2004

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Lymphoid Enhancer Factor-1 Links Two Hereditary Leukemia Syndromes through Core-binding Factor Regulation of ELA2^*

Feng-Qian Li, Richard E. Person, Ken-Ichi Takemaru, Kayleen Williams, Kimberly Meade-White, Ayse H. Ozsahin¶, Tayfun Güngör||, Randall T. Moon, and Marshall Horwitz**

From the Division of Medical Genetics, Department of Medicine, Howard Hughes Medical Institute, Department of Pharmacology, and Center for Developmental Biology, University of Washington School of Medicine, Seattle, Washington 98195-7720, ^¶University Hospitals of Geneva, 6 rue Willy Donzé, 1211 Geneva 14, Switzerland, and ^||University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland

Two hereditary human leukemia syndromes are severe congenital neutropenia (SCN), caused by mutations in the gene ELA2, encoding the protease neutrophil elastase, and familial platelet disorder with acute myelogenous leukemia (AML), caused by mutations in the gene AML1, encoding the transcription factor core-binding factor (CBF). In mice, CBF regulates the expression of ELA2, suggesting a common link for both diseases. However, gene-targeted mouse models have failed to reproduce either human disease, thus prohibiting further in vivo studies in mice. Here we investigate CBF regulation of the human ELA2 promoter, taking advantage of bone marrow obtained from patients with either illness. In particular, we have identified novel ELA2 promoter substitutions (-199 C to A) within a potential motif for lymphoid enhancer factor-1 (LEF-1), a transcriptional mediator of Wnt/-catenin signaling, in SCN patients. The LEF-1 motif lies adjacent to a potential CBF binding site that is in a different position in human compared with mouse ELA2. We find that LEF-1 and CBF co-activate ELA2 expression. In vitro, the high mobility group domain of LEF-1 interacts with the runt DNA binding and proline-, serine-, threonine-rich activation domains of CBF. ELA2 transcript levels are up-regulated in bone marrow of an SCN patient with the -199 C to A substitution. Conversely, a mutation of the CBF activation domain, found in a patient with familial platelet disorder with AML, fails to stimulate the ELA2 promoter in vitro, and bone marrow correspondingly demonstrates reduced ELA2 transcript. Observations in these complementary patients indicate that LEF-1 cooperates with CBF to activate ELA2 in vivo and also suggest the possibility that up-regulating promoter mutations can contribute to SCN. Two hereditary AML predisposition syndromes may therefore intersect via LEF-1, potentially linking them to more generalized cancer mechanisms.

Received for publication, September 30, 2003 , and in revised form, October 31, 2003.

^* This work was supported by National Institutes of Health Grants DK55820 and DK58161 and Burroughs-Wellcome Fund Grant SATR-1002189. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Division of Medical Genetics, Dept. of Medicine, University of Washington School of Medicine, 1705 N.E. Pacific St., HSB-K236B, Seattle, WA 98195-7720. Tel.: 206-616-4566; Fax: 206-616-7288; E-mail: horwitz{at}u.washington.edu.

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