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

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.

• Authors: H Uchida, J R Downing, Y Miyazaki, R Frank, J Zhang, S D Nimer
• Journal: Oncogene (Oncogene) Vol. 18 Issue 4 Pg. 1015-22 (Jan 28 1999) ISSN: 0950-9232 [Print] England
• PMID: 10023677 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Core Binding Factor Alpha 2 Subunit
• Interleukin-3
• Neoplasm Proteins
• Oncogene Proteins, Fusion
• Repressor Proteins
• TEL-AML1 fusion protein

Topics

• Child
• Core Binding Factor Alpha 2 Subunit
• Humans
• Interleukin-3 (chemistry, metabolism)
• Neoplasm Proteins (chemistry, genetics, physiology)
• Oncogene Proteins, Fusion
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics)
• Repressor Proteins (chemistry, genetics, physiology)
• Transcriptional Activation
• Translocation, Genetic