Lymphodepletion in the ApcMin/+ mouse model of intestinal tumorigenesis.
Germ line mutations in the Adenomatous polyposis coli tumor suppressor gene cause a hereditary form of intestinal tumorigenesis in both mice and man. Here we show that in Apc(Min/+) mice, which carry a heterozygous germ line mutation at codon 850 of Apc, there is progressive loss of immature and mature thymocytes from approximately 80 days of age with complete regression of the thymus by 120 days. In addition, Apc(Min/+) mice show parallel depletion of splenic natural killer (NK) cells, immature B cells, and B progenitor cells in bone marrow due to complete loss of interleukin 7 (IL-7)-dependent B-cell progenitors. Using bone marrow transplantation experiments into wild-type recipients, we have shown that the capacity of transplanted Apc(Min/+) bone marrow cells for T- and B-cell development appears normal. In contrast, although the Apc(Min/+) bone marrow microenvironment supported short-term reconstitution with wild-type bone marrow, Apc(Min/+) animals that received transplants subsequently underwent lymphodepletion. Fibroblast colony-forming unit (CFU-F) colony assays revealed a significant reduction in colony-forming mesenchymal progenitor cells in the bone marrow of Apc(Min/+) mice compared with wild-type animals prior to the onset of lymphodepletion. This suggests that an altered bone marrow microenvironment may account for the selective lymphocyte depletion observed in this model of familial adenomatous polyposis.
Coletta
P Louise
PL
Molecular Medicine Unit, Clinical Sciences Building, St James's University Hospital, Leeds LS9 7TF, United Kingdom. p.l.coletta@leeds.ac.uk
Müller
Albrecht M
AM
Jones
Elena A
EA
Mühl
Bettina
B
Holwell
Sarah
S
Clarke
Deborah
D
Meade
Josephine L
JL
Cook
Graham P
GP
Hawcroft
Gillian
G
Ponchel
Frederique
F
Lam
Wai K
WK
MacLennan
Ken A
KA
Hull
Mark A
MA
Bonifer
Constanze
C
Markham
Alexander F
AF
D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000818:Animals; D001284:Atrophy; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005260:Female; D017491:Genes, APC; D018095:Germ-Line Mutation; D006410:Hematopoiesis; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D016131:Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology