title: A lack of DNA mismatch repair on an athymic murine background predisposes to hematologic malignancy.
abstract: Inheritance of a germline mutation in one of the DNA mismatch repair genes predisposes human individuals to hereditary nonpolyposis colorectal cancer, characterized by development of tumors predominantly in the colon, endometrium, and gastrointestinal tract. Mice heterozygous for a mismatch repair-null mutation generally do not have an increased risk of neoplasia. However, mice constitutively lacking mismatch repair are prone to tumor development from an early age, particularly thymic lymphomas. Mismatch repair-deficient mice crossed to Apc(+/-) mice develop an increased spontaneous intestinal tumor incidence, demonstrating that the tumor spectrum can be genetically influenced. Here, we bred Msh2- and Msh6-deficient mice to athymic nude mice, hypothesizing that a broader tumor spectrum may be observed if mice are able to survive longer without succumbing to thymic lymphomas. However, Msh2(-/-);Foxn1(nu/nu) and Msh6(-/-);Foxn1(nu/nu) mice developed primarily early-onset lymphoblastic lymphomas. Using B-cell-specific markers, we found these tumors to be predominately B-cell in origin. The development of hematologic malignancy in the mouse, even in the absence of a thymus, parallels the development of B- and T-cell lymphoma and leukemia in the few rare mismatch repair-null human patients that have been identified. The persistent development of hematologic malignancy both in the mouse and in human patients deficient in mismatch repair leads us to implicate mismatch repair as an important repair mechanism in normal B- and T-cell development. Thus, mismatch repair-deficient mice may prove to be a good model to study human hematologic malignancy.
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Marcia R
authors.initials: MR
authors.lastname: Campbell
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Nation
authors.forename: Susan E
authors.initials: SE
authors.lastname: Andrew
mesh_terms: D000818:Animals; D003106:Colon / Q000473:pathology; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D018895:Microsatellite Repeats / Q000235:genetics; D051718:MutS Homolog 2 Protein; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C102997:Msh6 protein, mouse; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C090140:Whn protein; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein