TEL-AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL.
The t(12;21)(p13;q22) translocation generates the TEL-AML1 (TEL, translocation-Ets-leukemia; AML1, acute myeloid leukemia-1) (ETV6-RUNX1) fusion product and is the most common chromosomal abnormality in pediatric leukemia. Our previous studies using a murine fetal liver transplantation model demonstrated that TEL-AML1 promotes the self-renewal of B-cell precursors in vitro and enhances the expansion of hematopoietic stem cells (HSCs) in vivo. This is consistent with the hypothesis that TEL-AML1 induces expansion of a preleukemic clone. Several studies have described domains within TEL-AML1 involved in the transcriptional regulation of specific target genes. However, it is unclear which of these domains is important for the activity of TEL-AML1 in preleukemic hematopoiesis. In order to examine this, we have generated a panel of deletion mutants and expressed them in HSCs. These experiments demonstrate that TEL-AML1 requires multiple domains from both TEL and AML1 to alter hematopoiesis. Furthermore, mutation of a single amino-acid residue within the runt homology domain of AML1, required for DNA binding, was sufficient to abrogate TEL-AML1 activity. These data suggest that TEL-AML1 acts as an aberrant transcription factor to perturb multiple pathways during hematopoiesis.
Morrow
M
M
Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College, London, UK.
Samanta
A
A
Kioussis
D
D
Brady
H J M
HJ
Williams
O
O
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D001665:Binding Sites; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry* / Q000502:physiology; D004247:DNA / Q000378:metabolism*; D019281:Dimerization; D018257:Helix-Loop-Helix Motifs; D006412:Hematopoietic Stem Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D015514:Oncogene Proteins, Fusion / Q000737:chemistry* / Q000502:physiology; D011289:Preleukemia / Q000209:etiology*; D050783:Proto-Oncogene Proteins c-ets / Q000737:chemistry*; D012097:Repressor Proteins / Q000737:chemistry*; D012190:Retroviridae / Q000235:genetics; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D004247:DNA; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C493726:Runx1 protein, mouse; C102421:TEL-AML1 fusion protein