Transcriptional repression of the neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein

Genyan Yang, Waleed Khalaf, Louis Van De Locht, Joop H. Jansen, Meihua Gao, Mary Ann Thompson, Bert A. Van Der Reijden, David H. Gutmann, Ruud Delwel, D. Clapp, Scott W. Hiebert

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Von Recklinghausen's disease is a relatively common familial genetic disorder characterized by inactivating mutations of the Neurofibromatosis-1 (NF1) gene that predisposes these patients to malignancies, including an increased risk for juvenile myelomonocytic leukemia. However, NF1 mutations are not common in acute myeloid leukemia (AML). Given that the RUNX1 transcription factor is the most common target for chromosomal translocations in acute leukemia, we asked if NF1 might be regulated by RUNX1. In reporter assays, RUNX1 activated the NF1 promoter and cooperated with C/EBPα and ETS2 to activate the NF1 promoter over 80-fold. Moreover, the t(8;21) fusion protein RUNX1-MTG8 (R/M), which represses RUNXl-regulated genes, actively repressed the NF1 promoter. R/M associated with the NF1 promoter in vivo and repressed endogenous NF1 gene expression. In addition, similar to loss of NF1, R/M expression enhanced the sensitivity of primary myeloid progenitor cells to granulocyte-macrophage colony-stimulating factor. Our results indicate that the NF1 tumor suppressor gene is a direct transcriptional target of RUNX1 and the t(8;21) fusion protein, suggesting that suppression of NF1 expression contributes to the molecular pathogenesis of AML.

Original languageEnglish (US)
Pages (from-to)5869-5879
Number of pages11
JournalMolecular and Cellular Biology
Volume25
Issue number14
DOIs
StatePublished - Jul 2005
Externally publishedYes

Fingerprint

Neurofibromatosis 1
Neoplasms
Proteins
Neurofibromatosis 1 Genes
Acute Myeloid Leukemia
Juvenile Myelomonocytic Leukemia
Myeloid Progenitor Cells
Genetic Translocation
Mutation
Inborn Genetic Diseases
Granulocyte-Macrophage Colony-Stimulating Factor
Tumor Suppressor Genes
Leukemia
Transcription Factors
Gene Expression

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Yang, G., Khalaf, W., Van De Locht, L., Jansen, J. H., Gao, M., Thompson, M. A., ... Hiebert, S. W. (2005). Transcriptional repression of the neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein. Molecular and Cellular Biology, 25(14), 5869-5879. https://doi.org/10.1128/MCB.25.14.5869-5879.2005

Transcriptional repression of the neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein. / Yang, Genyan; Khalaf, Waleed; Van De Locht, Louis; Jansen, Joop H.; Gao, Meihua; Thompson, Mary Ann; Van Der Reijden, Bert A.; Gutmann, David H.; Delwel, Ruud; Clapp, D.; Hiebert, Scott W.

In: Molecular and Cellular Biology, Vol. 25, No. 14, 07.2005, p. 5869-5879.

Research output: Contribution to journalArticle

Yang, G, Khalaf, W, Van De Locht, L, Jansen, JH, Gao, M, Thompson, MA, Van Der Reijden, BA, Gutmann, DH, Delwel, R, Clapp, D & Hiebert, SW 2005, 'Transcriptional repression of the neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein', Molecular and Cellular Biology, vol. 25, no. 14, pp. 5869-5879. https://doi.org/10.1128/MCB.25.14.5869-5879.2005
Yang, Genyan ; Khalaf, Waleed ; Van De Locht, Louis ; Jansen, Joop H. ; Gao, Meihua ; Thompson, Mary Ann ; Van Der Reijden, Bert A. ; Gutmann, David H. ; Delwel, Ruud ; Clapp, D. ; Hiebert, Scott W. / Transcriptional repression of the neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein. In: Molecular and Cellular Biology. 2005 ; Vol. 25, No. 14. pp. 5869-5879.
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