The chimeric genes AML1/MDS1 and AML1/EAP inhibit AML1B activation at the CSF1R promoter, but only AML1/MDS1 has tumor-promoter properties

Clive S. Zent, Carol Mathieu, David F. Claxton, Dong Er Zhang, Daniel G. Tenen, Janet D. Rowley, Giuseppina Nucifora

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Abstract

The (3;21) (q26;q22) translocation associated with treatment-related myelodysplastic syndrome, treatment-related acute myeloid leukemia, and blast crisis of chronic myeloid leukemia results in the expression of the chimeric genes AML1/EAP, AML1/MDS1, and AML1/EVI1. AML1 (CBFA2), which codes for the α subunit of the heterodimeric transcription factor CBF, is also involved in the t(8;21), and the gene coding for the β subunit (CBFB) is involved in the inv(16). These are two of the most common recurring chromosomal rearrangements in acute myeloid leukemia. CBF corresponds to the murine Pebp2 factor, and CBF binding sites are found in a number of eukaryotic and viral enhancers and promoters. We studied the effects of AML1/EAP and AML1/MDS1 at the AML1 binding site of the CSF1R (macrophage-colony-stimulating factor receptor gene) promoter by using reporter gene assays, and we analyzed the consequences of the expression of both chimeric proteins in an embryonic rat fibroblast cell line (Rat1A) in culture and after injection into athymic nude mice. Unlike AML1, which is an activator of the CSF1R promoter, the chimeric proteins did not transactivate the CSF1R promoter site but acted as inhibitors of AML1 (CBFA2). AML1/EAP and AML1/MDS1 expressed in adherent Rat1A cells decreased contact inhibition of growth, and expression of AML1/MDS1 was associated with acquisition of the ability to grow in suspension culture. Expression of AML1/MDS1 increased the tumorigenicity of Rat1A cells injected into athymic nude mice, whereas AML1/EAP expression prevented tumor growth. These results suggest that expression of AML1/EAP and AML1/MDS1 can interfere with normal AML1 function, and that AML1/MDS1 has tumor-promoting properties in an embryonic rat fibroblast cell line.

Original languageEnglish (US)
Pages (from-to)1044-1048
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number3
DOIs
StatePublished - Feb 6 1996
Externally publishedYes

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Nude Mice
Carcinogens
Acute Myeloid Leukemia
Genes
Fibroblasts
Macrophage Colony-Stimulating Factor Receptors
Binding Sites
Contact Inhibition
Blast Crisis
Cell Line
Myelodysplastic Syndromes
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Growth
Reporter Genes
Neoplasms
Suspensions
Proteins
Transcription Factors
Gene Expression
Injections

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The chimeric genes AML1/MDS1 and AML1/EAP inhibit AML1B activation at the CSF1R promoter, but only AML1/MDS1 has tumor-promoter properties. / Zent, Clive S.; Mathieu, Carol; Claxton, David F.; Zhang, Dong Er; Tenen, Daniel G.; Rowley, Janet D.; Nucifora, Giuseppina.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 3, 06.02.1996, p. 1044-1048.

Research output: Contribution to journalArticle

Zent, Clive S. ; Mathieu, Carol ; Claxton, David F. ; Zhang, Dong Er ; Tenen, Daniel G. ; Rowley, Janet D. ; Nucifora, Giuseppina. / The chimeric genes AML1/MDS1 and AML1/EAP inhibit AML1B activation at the CSF1R promoter, but only AML1/MDS1 has tumor-promoter properties. In: Proceedings of the National Academy of Sciences of the United States of America. 1996 ; Vol. 93, No. 3. pp. 1044-1048.
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abstract = "The (3;21) (q26;q22) translocation associated with treatment-related myelodysplastic syndrome, treatment-related acute myeloid leukemia, and blast crisis of chronic myeloid leukemia results in the expression of the chimeric genes AML1/EAP, AML1/MDS1, and AML1/EVI1. AML1 (CBFA2), which codes for the α subunit of the heterodimeric transcription factor CBF, is also involved in the t(8;21), and the gene coding for the β subunit (CBFB) is involved in the inv(16). These are two of the most common recurring chromosomal rearrangements in acute myeloid leukemia. CBF corresponds to the murine Pebp2 factor, and CBF binding sites are found in a number of eukaryotic and viral enhancers and promoters. We studied the effects of AML1/EAP and AML1/MDS1 at the AML1 binding site of the CSF1R (macrophage-colony-stimulating factor receptor gene) promoter by using reporter gene assays, and we analyzed the consequences of the expression of both chimeric proteins in an embryonic rat fibroblast cell line (Rat1A) in culture and after injection into athymic nude mice. Unlike AML1, which is an activator of the CSF1R promoter, the chimeric proteins did not transactivate the CSF1R promoter site but acted as inhibitors of AML1 (CBFA2). AML1/EAP and AML1/MDS1 expressed in adherent Rat1A cells decreased contact inhibition of growth, and expression of AML1/MDS1 was associated with acquisition of the ability to grow in suspension culture. Expression of AML1/MDS1 increased the tumorigenicity of Rat1A cells injected into athymic nude mice, whereas AML1/EAP expression prevented tumor growth. These results suggest that expression of AML1/EAP and AML1/MDS1 can interfere with normal AML1 function, and that AML1/MDS1 has tumor-promoting properties in an embryonic rat fibroblast cell line.",
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AU - Mathieu, Carol

AU - Claxton, David F.

AU - Zhang, Dong Er

AU - Tenen, Daniel G.

AU - Rowley, Janet D.

AU - Nucifora, Giuseppina

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