Interferon Regulatory Factor-8 Is Indispensable for the Expression of Promyelocytic Leukemia and the Formation of Nuclear Bodies in Myeloid Cells

Abstract

Interferon (IFN) regulatory factor-8 (IRF-8), previously known as ICSBP, is a myeloid cell essential transcription factor. Mice with null mutation in IRF-8 are defective in the ability of myeloid progenitor cells to mature toward macrophage lineage. Accordingly, these mice develop chronic myelogenous leukemia (CML). We demonstrate here that IRF-8 is an obligatory regulator of the promyelocytic leukemia (PML) gene in activated macrophages, leading to the expression of the PML-I isoform. This regulation is most effective together with two other transcription factors, IRF-1 and PU.1. PML is a tumor suppressor gene that serves as a scaffold protein for nuclear bodies. IRF-8 is not only essential for the IFN-␥-induced expression of PML in activated macrophages but also for the formation of nuclear bodies. Reduced IRF-8 transcript levels were reported in CML patients, and a recovery to normal levels was observed in patients in remission following treatment with IFN-␣. We demonstrate a significant correlation between the levels of IRF-8 and PML in these CML patients. Together, our results indicate that some of the myeloleukemia suppressor activities of IRF-8 are mediated through the regulation of PML. When IRF-8 levels are compromised, the reduced PML expression may lead to genome instability and eventually to the leukemic phenotype.

Interferon Regulatory Factor 8 (IRF8) Interacts with the B Cell Lymphoma 6 (BCL6) Corepressor BCOR

“…An analysis of the interactions between IRF8 and BCOR demonstrated a requirement for the C-terminal region of IRF8, which contains an ␣-helix protein-protein interaction domain, and the N-terminal region of BCOR, which contains the sequences required for BCL6 binding. Accumulation in the cytoplasm of IRF8 mutant protein lacking the ␣-helix region clearly supports previous observations of IRF8 function and interaction with partner proteins in the nucleus (37,38).…”

Regulation of the PML tumor suppressor in drug-induced senescence of human normal and cancer cells by JAK/STAT-mediated signaling

“…30 Since overexpression of IRF1 leads to elevated PML transcripts, 80 increased levels of IRF1 found after drug treatment 35 may contribute to JAK/STAT-dependent PML expression in our present study. Moreover, ATM-dependent stabilization of IRF1 was reported after etoposide treatment, 81 and precise characterization sensitivity of BrdU-treated cells to light-induced DNA damage, cells were exposed to light only for minimal time periods necessary for handling.…”

The Interferon Regulatory Factor Family in Host Defense: Mechanism of Action

“…Given that PML and Sp100 are induced by IFN through ISREs, involvement of IRFs in nuclear body activity has been expected. Indeed, recent studies show that IRF-8 is required for the expression of PML and Sp100 in macrophages and DCs, where nuclear bodies are larger and more intense than in other cell types (6,29). In light of the predominant role of macrophages and DCs in the control of viral infection, IRF-8 and other IRFs may play a role in PMLmediated host antiviral responses.…”