Conditional inactivation of MLH1 in thymic and naive T-cells in mice leads to a limited incidence of lymphoblastic T-cell lymphomas

Abstract

Defects in the mismatch repair system (MMR) underlie hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome and also a significant number of sporadic colorectal cancers. Mice carrying a null allele for the MMR gene Mlh1 are preferentially prone to the development of lymphomas of B- and T-cell origin and to a lesser extent gastrointestinal tumors. Consistent with these findings in mice, MMR defects have also been observed in sporadic and hereditary hematological malignancies. To study the role of MLH1 for lymphomagenesis in more detail, we generated a new mouse model carrying a conditional Mlh1 allele (Mlh1^flox/flox). Mating of these mice with EIIa-Cre recombinase transgenic mice allowed the constitutive inactivation of MLH1, and the resulting Mlh1^Δex4/Δex4 mouse line displays complete MMR deficiency and a cancer predisposition phenotype similar to Mlh1^−/− mice. For T-cell specific MMR inactivation we combined the Mlh1^flox/flox allele with the Lck-Cre transgene. In the resulting Mlh1^{TΔex4/TΔex4} mice, MLH1 inactivation is limited to DP/SP thymocytes and naive peripheral T-cells. The development of T-cell lymphomas in Mlh1^{TΔex4/TΔex4} mice is significantly reduced compared to Mlh1^−/− mice, implying that MMR functions either at very early stages during T-cell development or even earlier in lymphoid precursor cells to suppress lymphomagenesis.

Keywords:

• Mismatch repair
• MLH1
• Lymphoblastic T-cell lymphoma
• Conditional mouse model
• Lck-Cre

Acknowledgements

We thank Martina Döhler for excellent technical support and Jacqueline Krämer for critically reading the manuscript.

Declaration of interest: This work was supported by grants from the ‘Interdisziplinäres Zentrum für Klinische Forschung (IZKF)’ at the Department of Medicine, University of Würzburg, Germany and the DFG graduate college 639.