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

Oncogene volume 22, pages 4581–4585 (2003)Cite this article

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.

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Acknowledgements

We appreciate the insightful comments and advice provided by Drs Jerrold Ward, D Wade Clapp, and Richard Burack during the execution and analysis of these experiments. This work was partially funded by grants from the National Institutes of Health (NS36996 to DHG and NIH R37 GM32741 to RML).

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Authors and Affiliations

  1. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

    D H Gutmann, E Winkeler & N Hedrick

  2. Department of Surgery, Washington University School of Medicine, St Louis, MO, USA

    O Kabbarah & P J Goodfellow

  3. Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA

    S Dudley & R M Liskay

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  1. D H Gutmann
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  2. E Winkeler
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Correspondence to D H Gutmann.

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Gutmann, D., Winkeler, E., Kabbarah, O. et al. Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice. Oncogene 22, 4581–4585 (2003). https://doi.org/10.1038/sj.onc.1206768

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