Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice

D. H. Gutmann, E. Winkeler, O. Kabbarah, N. Hedrick, S. Dudley, P. J. Goodfellow, R. M. Liskay

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21 Scopus citations

Abstract

Defects in DNA mismatch repair (MMR) have been implicated in the genesis of a diverse set of human cancers. Recent studies have suggested that one of the targets of MMR is the neurofibromatosis 1 (NF1) gene. To evaluate the contribution of Mlh1 MMR deficiency to Nf1 tumorigenesis, Mlh1-/-; Nf1+/- mice were generated. All Mlh1-/-;Nf1+/- mice (n = 21) were dead by 260 days compared to none of the Nf1+/- mice. In all, 50% of the Mlh1-/-;Nf1+/- mice were dead at 150 days compared to 252 days for Mlh1-/- mice. Nine of the Mlh1-/-;Nf1+/- mice were found to harbor intrathoracic NOS2-immunoreactive myeloid leukemias similar to the hematopoietic malignancies observed in older Nf1+/- mice. As expected, significant microsatellite instability was observed in six of six tumors and neurofibromin expression was lost in all tumors analysed. These results suggest that MMR deficiency can accelerate myeloid leukemogenesis in Nf1+/- mice, presumably by inactivating Nf1 gene expression.

Original languageEnglish (US)
Pages (from-to)4581-4585
Number of pages5
JournalOncogene
Volume22
Issue number29
DOIs
StatePublished - Jul 17 2003

Keywords

  • Leukemia
  • Mismatch repair
  • Neurofibromin
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Gutmann, D. H., Winkeler, E., Kabbarah, O., Hedrick, N., Dudley, S., Goodfellow, P. J., & Liskay, R. M. (2003). Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice. Oncogene, 22(29), 4581-4585. https://doi.org/10.1038/sj.onc.1206768