The role of HIF-1a in the development of lymphoproliferative diseases in transgenic mouse model

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Hypoxia-inducible factor-1alfa (HIF-1 alfa) plays an important role in the induction of various genes under hypoxic condition. We investigate the role of HIF-1 alfa in tumor development and metastasis, and established transgenic mice constitutively expressing HIF-1A gene under regulation of the cytomegalovirus gene promoter. HIF-1 alfa protein levels varied among organs, but the expression of HIF-1 alfa mRNA gradually increased in an age-dependent manner. The transgenic mice developed tumors in the lymphoid, lung, and breast; the most prominent tumor was lymphoma appearing in the intestinal mucosa and intra-mesenchymal tissues. The lymphocytes of the transgenic mice revealed prolonged survival under long-term culture conditions and revealed increased resistance to cytotoxic drugs. These results suggest that HIF-1 alfa play an important role in lymphomagenesis mediated through the prolonged survival of lymphocytes in this transgenic mouse model.