Chronic myelogeneous leukemia (CML) is a myeloid proliferative disease featured in a chronic stage of clonal expansion of undifferentiated myeloid cells followed by an accelerated stage with uncontrolled clonal expansion of blastocytes that quickly progresses to blast crisis. IFN regulatory factor 8 (IRF8) is a key transcription factor for myeloid cell differentiation and its expression is frequently lost in hematopoietic cells of human myeloid leukemia patients. IRF8-deficient mice exhibit similar symptoms to human CML patients with accumulation of undifferentiated myeloid cells in the bone marrow and periphery blood that can progress to a fatal blast crisis, thus IRF8 is a myeloid leukemia suppressor. Although the role of IRF8 function in CML has highly appreciated, the molecular mechanisms underlying IRF8 function in CML are still largely unknown. In this study, we use IRF8 knockout mice as proof of study. We observed that Bax expression level is low in bone marrow progenitor cells and increases dramatically in primary myeloid cells in wt mice. In contrast, Bax expression level remained at a low level in primary myeloid cells in IRF8 KO mice. However, in vitro IRF8 KO bone marrow-differentiated myeloid cells expressed Bax at a level as high as that in wild type myeloid cells. Furthermore, we demonstrated that IRF8 specifically binds to the Bax promoter region in primary myeloid cells. Functional analysis showed that IRF8 deficiency results in increased resistance of the primary myeloid cells to Fas-mediated apoptosis, which indicates that CML cells could use the strategy of silencing IRF8 to downregulate pro-apoptotic gene Bax to acquire apoptosis resistance. To summarize, our findings show that IRF8 directly regulates Bax transcription in vivo, but not in vitro during myeloid cell lineage differentiation and silencing IRF8 to disrupt apoptosis related genes expression could result in uncontrolled clonal expansion of myeloid cells and leukemia development.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2014. doi:1538-7445.AM2012-2014