Missing mismatch repair: a key to T cell immortality

The mismatch repair (MMR) pathway maintains the integrity of the genome by repairing DNA mismatches or loops caused by insertion or deletion of nucleotides, which can be caused by DNA replication, oxidative damage, cytidine deamination, or chemical mutagens. The MMR pathway also maintains the fidelity of the genome by inhibiting recombination between non-identical sequences, and induces apoptosis in response to high levels of DNA damage [1]. Thus, deficiency in MMR can promote cellular transformation through multiple mechanisms.

Tumors that are deficient in MMR are characterized by an instability of short tandem DNA repeated sequences known as microsatellites [2]. Microsatellite instability (MSI) is a hallmark of the hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, but is also observed in many sporadic cancers including hematological malignances [3–6]. Abnormal chromosomal rearrangements give rise to most of the hematological tumors. In this regard, it has been suggested that MMR protects from recombination between divergent DNA sequences by recognizing and binding DNA mismatches [7]. A compromised MMR pathway might therefore create a genomic environment that allows for the development of hematological cancers by increasing the rate of chromosomal rearrangements during T and B cell development [7]. Recently, it has been shown that the biallelic loss of Msh2, the central protein in MMR, was critical to the development of HNPCC-related lymphomas [8]. This discovery raised further questions about the specific role of other genes involved in the MMR pathway in hematological tumors associated with MSI and colorectal cancer.

In this issue of Leukemia and Lymphoma, Reiss and colleagues [9] provide key insights into the role of MLH1, an important component of the MMR pathway, in the development of T cell lymphoma. Using a gene targeting strategy, the authors developed an Mlh1 exon 4 allele that was flanked with loxP sites. This mouse model was then used to specifically delete MLH1 from the T cell compartment (i.e. Mlh1^{TΔex4/TΔex4}) in order to examine the development of T cell lymphomas and avoid the overlaying effects of tumorigenesis in other cellular systems. The resulting Mlh1^{TΔex4/TΔex4} mice showed a reduced tumor predisposition phenotype compared to Mlh1^−/− mice; only 6% of Mlh1^{TΔex4/TΔex4} mice developed lymphoma after 40 weeks of age compared to 26% of Mlh1^−/− mice. In addition, tumors from Mlh1^{TΔex4/TΔex4} mice developed primarily from double positive (CD4 + /CD8 + ) T cell lymphocytes. This finding contrasts with the observation that T lymphomas in Mlh1^−/− mice occur at many different stages of development. Taken together, the results presented by Reiss and colleagues provide novel evidence that MMR plays a critical role in preventing genetic events that lead to cellular transformation at very early stages, either during T cell development or at earlier stages of hematopoietic development. These data support a recent report that showed that Msh2 plays a critical tumor suppressive role in early B cell precursors [10]. The question of why the deletion of Mlh1 in thymocytes leads to precursor T cell lymphomas while deletion of Mlh1 in all tissues leads to precursor and mature T cell lymphomas will likely be the subject of further investigation.

The discovery that the MMR pathway prevents oncogenic events that arise early in T cell development could explain the relatively rare cases of lymphomagenesis in heterozygous patients with HNPCC/Lynch syndrome. Loss of both copies of specific MMR genes and complete inactivation of MMR in such patients occurs later in their life when T cell production is significantly reduced. Ultimately, the Mlh1 exon 4 conditional mouse described in this issue of Leukemia and Lymphoma by Reiss and colleagues could be a useful tool for investigating the effects of MMR deletion at specific stages of B or T lymphopoiesis, or in other tissues such as colon epithelial cells. Establishing conditional gene inactivation models has been beneficial for the generation of highly specific tumors at high incidence, and these serve as excellent models for testing new therapeutics and diagnostics or establishing preventive measures.