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

Bernd B. Zeisig, Tom Milne, María Paz García-Cuéllar, Silke Schreiner, Mary Ellen Martin, Uta Fuchs, Arndt Borkhardt, Sumit K. Chanda, John Walker, Richard Soden, Jay Hess, Robert K. Slany

Research output: Contribution to journalArticle

230 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)617-628
Number of pages12
JournalMolecular and Cellular Biology
Volume24
Issue number2
DOIs
StatePublished - Jan 2004
Externally publishedYes

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Lymphoid Leukemia
Myeloid Leukemia
Homeobox Genes
Tamoxifen
Microarray Analysis
Growth
Leukemia
Proteins
Transcription Factors
afimoxifene

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Zeisig, B. B., Milne, T., García-Cuéllar, M. P., Schreiner, S., Martin, M. E., Fuchs, U., ... Slany, R. K. (2004). Hoxa9 and Meis1 Are Key Targets for MLL-ENL-Mediated Cellular Immortalization. Molecular and Cellular Biology, 24(2), 617-628. https://doi.org/10.1128/MCB.24.2.617-628.2004

Hoxa9 and Meis1 Are Key Targets for MLL-ENL-Mediated Cellular Immortalization. / Zeisig, Bernd B.; Milne, Tom; García-Cuéllar, María Paz; Schreiner, Silke; Martin, Mary Ellen; Fuchs, Uta; Borkhardt, Arndt; Chanda, Sumit K.; Walker, John; Soden, Richard; Hess, Jay; Slany, Robert K.

In: Molecular and Cellular Biology, Vol. 24, No. 2, 01.2004, p. 617-628.

Research output: Contribution to journalArticle

Zeisig, BB, Milne, T, García-Cuéllar, MP, Schreiner, S, Martin, ME, Fuchs, U, Borkhardt, A, Chanda, SK, Walker, J, Soden, R, Hess, J & Slany, RK 2004, 'Hoxa9 and Meis1 Are Key Targets for MLL-ENL-Mediated Cellular Immortalization', Molecular and Cellular Biology, vol. 24, no. 2, pp. 617-628. https://doi.org/10.1128/MCB.24.2.617-628.2004
Zeisig BB, Milne T, García-Cuéllar MP, Schreiner S, Martin ME, Fuchs U et al. Hoxa9 and Meis1 Are Key Targets for MLL-ENL-Mediated Cellular Immortalization. Molecular and Cellular Biology. 2004 Jan;24(2):617-628. https://doi.org/10.1128/MCB.24.2.617-628.2004
Zeisig, Bernd B. ; Milne, Tom ; García-Cuéllar, María Paz ; Schreiner, Silke ; Martin, Mary Ellen ; Fuchs, Uta ; Borkhardt, Arndt ; Chanda, Sumit K. ; Walker, John ; Soden, Richard ; Hess, Jay ; Slany, Robert K. / Hoxa9 and Meis1 Are Key Targets for MLL-ENL-Mediated Cellular Immortalization. In: Molecular and Cellular Biology. 2004 ; Vol. 24, No. 2. pp. 617-628.
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