Normal lymphocyte development and thymic lymphoma formation in Brca1 exon-11-deficient mice

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Abstract
Breast-cancer-associated gene 1 (BRCA1) is highly expressed in thymus and spleen. In this paper, we have studied lymphocyte development and tumorigenesis in mice carrying mutations in Brca1 and p53. We show that the deletion of Brca1 exon 11 (Brca1-Δ11), which disrupts the full-length isoform, but not the short isoform of Brca1, does not interfere with lymphocyte development. This is true irrespective of p53 status, that is, whether it is wild type, heterozygous or homozygous for a null mutation. These data suggest that the expression of Brca1 short isoform alone is enough to maintain normal development of lymphocytes. However, it cannot suppress tumorigenesis as about 30% of Brca1Δ11/Δ11p53+/− mice develop thymic lymphoma between 3 and 7 months of age. We demonstrate that p53 plays an essential role in Brca1-associated lymphoma, as all the tumors from Brca1Δ11/Δ11p53+/− mice exhibit LOH of p53 and Brca1Δ11/Δ11p53−/− mice exhibited accelerated tumorigenesis. We further demonstrate that the Brca1-Δ11 deficiency does not affect thymocyte proliferation; however, it increases genetic instability and triggers γ-irradiation-induced apoptosis. The loss of p53 attenuates apoptosis and allows accumulation of further mutations in Brca1-Δ11 thymocytes, eventually leading to thymic lymphoma formation.