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PMID: 14701735 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization.

Molecular and cellular biology ·Vol. 24 ·No. 2 ·2004-01-00 ·Pages 617-28

Zeisig BB, Milne T, García-Cuéllar MP, Schreiner S, Martin ME, Fuchs U, Borkhardt A, Chanda SK, Walker J, Soden R, Hess JL, Slany RK

Abstract

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.

MeSH Terms
Animals Cell Line Cell Transformation, Neoplastic/drug effects,genetics,metabolism Down-Regulation Genes, Homeobox Homeodomain Proteins/genetics Humans Leukemia/genetics,metabolism Mice Myeloid Ecotropic Viral Integration Site 1 Protein Myeloid-Lymphoid Leukemia Protein Neoplasm Proteins/genetics Oncogene Proteins, Fusion/genetics,metabolism Receptors, Estrogen/genetics,metabolism Tamoxifen/analogs & derivatives,pharmacology Up-Regulation
Chemicals
Homeodomain Proteins MEIS1 protein, human MLL-ENL oncoprotein, human Meis1 protein, mouse Myeloid Ecotropic Viral Integration Site 1 Protein Neoplasm Proteins Oncogene Proteins, Fusion Receptors, Estrogen homeobox protein HOXA9 Tamoxifen Myeloid-Lymphoid Leukemia Protein afimoxifene
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Zeisig Bernd B
Department of Genetics, University Erlangen, Staudtstrasse 5, 91058 Erlangen, Germany.
Milne Tom
García-Cuéllar María-Paz
Schreiner Silke
Martin Mary-Ellen
Fuchs Uta
Borkhardt Arndt
Chanda Sumit K
Walker John
Soden Richard
Hess Jay L
Slany Robert K
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.2.617-628.2004
Published
2004-01-00
Pages
617-28
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC343796
Subset
IM
Grants
NCI NIH HHS · R01 CA092251 · United States
NCI NIH HHS · CA 92251 · United States
External Links
PubMed source DOI: 10.1128/MCB.24.2.617-628.2004 PMC Full Text View journal details
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