Hypoxia-inducible factor-1α (HIF-1α) has a central role on regulation of various genes under hypoxic condition linked to regulation of angiogenesis, metabolism and tumor development. Expression of HIF-1α was reported in many cancers associated with tumor progression, invasion and metastasis. We reported that constitutive expression of HIF-1α in transgenic mice induced tumors in lymphoid, lung and breast tissues in last this meeting. The incidence of tumors in transgenic mice was up to 90% until 18 months after birth. To clarify the molecular mechanism of lymphomagenesis in the transgenic mice, lymphocyte subsets, gene expression and mitogenic responsiveness on lymphoid tissues were analyzed. Although population of T and B cell subset in spleen, maturation pattern of T cells in thymus, or cell growth rate after treatment with various mitogens were not changed by HIF-1α overexpression, the lymphocytes from transgernic mice showed longer survival than those from wild mice. The lymphocytes also showed resistance for genotoxic stimuli like topoisomerase inhibitors. We next compared gene expression profile on lymphocyte from transgenic mice and wild mice by cDNA microarray and RT-PCR. The expression of over a hundred of genes including HIF-1α itself was altered on T and B cells in transgenic mice. Among them the gene associated with cell survival and cell transformation-related genes were further analyzed by validation study. In this paper, we present the results concerning the role of HIF-1α in lymphoma occurrence, and will discuss the contribution of the transcription factor in human cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3093. doi:10.1158/1538-7445.AM2011-3093