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  • Original Paper
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Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter

Oncogene volume 18, pages 1015–1022 (1999)Cite this article

Abstract

A cytogenetically cryptic (12;21) translocation is the most common molecular abnormality identified in childhood acute lymphoblastic leukemia (ALL), and it generates a chimeric TEL-AML1 protein. Fusion of the Helix-Loop-Helix (HLH) (also called the pointed) domain of TEL to AML1 has been suggested to convert AML1 from a transcriptional activator to a repressor. To define the structural features of this chimeric protein required for repression, we analysed the transcriptional activity of a series of TEL-AML1 mutants on the AML1-responsive interleukin-3 (IL-3) promoter, a potentially relevant gene target. Our results demonstrate that TEL-AML1 represses basal IL-3 promoter activity in lymphoid cells, and deletion mutant analysis identified three distinct domains of TEL-AML1 that are required for repression; the HLH (pointed) motif contained in the TEL portion of TEL-AML1, and both the runt homology domain (Rhd) and the 74 amino acids downstream of the Rhd that are present in the AML1 portion of the fusion protein. Although AML1B (and a shorter AML1 isoform, AML1A) have transcriptional activating activity on the IL-3 promoter, fusion of the AML1 gene to the TEL gene generates a repressor of IL-3 expression. Consistent with this activity, freshly isolated human ALL cells that contain TEL-AML1 do not express IL-3.

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Acknowledgements

We thank Olga Shadrin for her assistance in preparing this manuscript. This work was supported by grants DK43025, DK 52208, and CA 70388 from the National Institutes of Health, and by funds from the DeWitt Wallace Foundation (SDN, RF) and the Norman and Rosita Winston Foundation (YM).

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Authors and Affiliations

  1. Laboratory of Molecular Aspects of Hematopoiesis, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, 10021, NY, New York, USA

    Hideo Uchida, Yasushi Miyazaki, Richard Frank, Jin Zhang & Stephen D Nimer

  2. Department of Pathology, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, 38109, Tennessee, USA

    James R Downing

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  1. Hideo Uchida
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Uchida, H., Downing, J., Miyazaki, Y. et al. Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter. Oncogene 18, 1015–1022 (1999). https://doi.org/10.1038/sj.onc.1202383

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