Lymphodepletion in the ApcMin/+ mouse model of intestinal tumorigenesis

Research output: Contribution to journalArticle

Authors

  • PL Coletta
  • AM Müller
  • EA Jones
  • B Mühl
  • S Holwell
  • D Clarke
  • JL Meade
  • GP Cook
  • G Hawcroft
  • F Ponchel
  • WK Lam
  • KA MacLennan
  • MA Hull
  • AF Markham

Colleges, School and Institutes

Abstract

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.

Details

Original languageEnglish
Pages (from-to)1050-8
Number of pages9
JournalBlood
Volume103
Issue number3
Publication statusPublished - 1 Feb 2004