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Molecular and Cellular Biology, January 2004, p. 617-628, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.617-628.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Hoxa9 and Meis1 Are Key Targets for MLL-ENL-Mediated Cellular Immortalization

Bernd B. Zeisig,1 Tom Milne,2 María-Paz García-Cuéllar,1 Silke Schreiner,1 Mary-Ellen Martin,2 Uta Fuchs,3 Arndt Borkhardt,3 Sumit K. Chanda,4 John Walker,4 Richard Soden,4 Jay L. Hess,2 and Robert K. Slany1*

Department of Genetics, University Erlangen, 91058 Erlangen,1 Department of Hematology & Oncology, Childrens Hospital, 35392 Giessen, Germany,3 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,2 Genomics Institute of the Novartis Research Foundation, San Diego, California 921214

Received 2 July 2003/ Returned for modification 30 September 2003/ Accepted 27 October 2003

MLL fusion proteins are oncogenic transcription factors that are associated with aggressive lymphoid and myeloid leukemias. We constructed an inducible MLL fusion, MLL-ENL-ERtm, that rendered the transcriptional and transforming properties of MLL-ENL strictly dependent on the presence of 4-hydroxy-tamoxifen. MLL-ENL-ERtm-immortalized hematopoietic cells required 4-hydroxy-tamoxifen for continuous growth and differentiated terminally upon tamoxifen withdrawal. Microarray analysis performed on these conditionally transformed cells revealed Hoxa9 and Hoxa7 as well as the Hox coregulators Meis1 and Pbx3 among the targets upregulated by MLL-ENL-ERtm. Overexpression of the Hox repressor Bmi-1 inhibited the growth-transforming activity of MLL-ENL. Moreover, the enforced expression of Hoxa9 in combination with Meis1 was sufficient to substitute for MLL-ENL-ERtm function and to maintain a state of continuous proliferation and differentiation arrest. These results suggest that MLL fusion proteins impose a reversible block on myeloid differentiation through aberrant activation of a limited set of homeobox genes and Hox coregulators that are consistently expressed in MLL-associated leukemias.

* Corresponding author. Mailing address: Department of Genetics, University Erlangen, Staudtstrasse 5, 91058 Erlangen, Germany. Phone: 49 (9131) 852-8527. Fax: 49 (9131) 852-5096. E-mail: rslany{at}biologie.uni-erlangen.de.

Molecular and Cellular Biology, January 2004, p. 617-628, Vol. 24, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.2.617-628.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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