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

Cora Reiss, Torsten Haneke, Hans Ulrich Völker, Martin Spahn, Andreas Rosenwald, Winfried Edelmann, Burkhard Kneitz

Research output: Contribution to journalArticle

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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 (Mlh1flox/flox). Mating of these mice with EIIa-Cre recombinase transgenic mice allowed the constitutive inactivation of MLH1, and the resulting Mlh1Δex4/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 Mlh1flox/flox allele with the Lck-Cre transgene. In the resulting Mlh1TΔex4/TΔex4 mice, MLH1 inactivation is limited to DP/SP thymocytes and naive peripheral T-cells. The development of T-cell lymphomas in Mlh1TΔex4/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.

Original languageEnglish (US)
Pages (from-to)1875-1886
Number of pages12
JournalLeukemia and Lymphoma
Volume51
Issue number10
DOIs
StatePublished - Oct 2010

Fingerprint

T-Cell Lymphoma
DNA Mismatch Repair
T-Lymphocytes
Incidence
Alleles
Colorectal Neoplasms
Hereditary Nonpolyposis Colorectal Neoplasms
B-Cell Lymphoma
Hematologic Neoplasms
Thymocytes
Transgenes
Transgenic Mice
Neoplasms
Lymphocytes
Phenotype

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Conditional inactivation of MLH1 in thymic and naive T-cells in mice leads to a limited incidence of lymphoblastic T-cell lymphomas. / Reiss, Cora; Haneke, Torsten; Völker, Hans Ulrich; Spahn, Martin; Rosenwald, Andreas; Edelmann, Winfried; Kneitz, Burkhard.

In: Leukemia and Lymphoma, Vol. 51, No. 10, 10.2010, p. 1875-1886.

Research output: Contribution to journalArticle

Reiss, Cora ; Haneke, Torsten ; Völker, Hans Ulrich ; Spahn, Martin ; Rosenwald, Andreas ; Edelmann, Winfried ; Kneitz, Burkhard. / Conditional inactivation of MLH1 in thymic and naive T-cells in mice leads to a limited incidence of lymphoblastic T-cell lymphomas. In: Leukemia and Lymphoma. 2010 ; Vol. 51, No. 10. pp. 1875-1886.
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AU - Rosenwald, Andreas

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