Conditional inactivation of MLH1 in thymic and naive T-cells in mice leads to a limited incidence of lymphoblastic T-cell lymphomas.
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.
Reiss
Cora
C
Physiological Chemistry I, University of Würzburg, Germany.
Haneke
Torsten
T
Völker
Hans-Ulrich
HU
Spahn
Martin
M
Rosenwald
Andreas
A
Edelmann
Winfried
W
Kneitz
Burkhard
B
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D004260:DNA Repair / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053842:Microsatellite Instability; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; C501485:Mlh1 protein, mouse; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1