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Hoxa9 and Meis1 Are Key Targets for MLL-ENL-Mediated Cellular Immortalization
Open accessAbstract
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.
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Cited by
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Krivtsov, A. V., Twomey, D., Feng, Z., Stubbs, M. C., Wang, Y., Faber, J., Levine, J. E., Wang, J., Hahn, W. C., Gilliland, D. G., et al. (2006) · Nature · doi:10.1038/nature04980 · Cited by 1,513
FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N 6 -Methyladenosine RNA Demethylase
Li, Z., Weng, H., Su, R., Weng, X., Zuo, Z., Li, C., Huang, H., Nachtergaele, S., Dong, L., Hu, C., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2016.11.017 · Cited by 1,508
Shilatifard, A. (2012) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-051710-134100 · Cited by 1,091
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Bernt, K. M., Zhu, N., Sinha, A. U., Vempati, S., Faber, J., Krivtsov, A. V., Feng, Z., Punt, N., Daigle, A., Bullinger, L., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.06.010 · Cited by 870
Yokoyama, A., Somervaille, T. C. P., Smith, K. S., Rozenblatt-Rosen, O., Meyerson, M., & Cleary, M. L. (2005) · Cell · doi:10.1016/j.cell.2005.09.025 · Cited by 688
Metadata
- Authors
- Zeisig, B. B., Milne, T., García-Cuéllar, M.-P., Schreiner, S., Martin, M.-E., Fuchs, U., Borkhardt, A., Chanda, S. K., Walker, J., Soden, R., Hess, J. L., & Slany, R. K.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2004-01-01
- Volume
- 24
- Issue
- 2
- Pages
- 617-628
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2157646587
- Cited by
- 328
- References
- 0
- FWCI
- 7.10
- Type
- journal article
- Language
- en
- Open access
- green
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- Zeisig, B. B., Milne, T., García-Cuéllar, M.-P., Schreiner, S., Martin, M.-E., Fuchs, U., Borkhardt, A., Chanda, S. K., Walker, J., Soden, R., Hess, J. L., & Slany, R. K. (2004). Hoxa9 and Meis1 Are Key Targets for MLL-ENL-Mediated Cellular Immortalization. Molecular and Cellular Biology. https://doi.org/10.1128/mcb.24.2.617-628.2004
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