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-gamma-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-alpha. 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.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Female
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Gene Expression Regulation, Leukemic* / genetics
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Genomic Instability* / genetics
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Humans
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Interferon Regulatory Factor-1 / genetics
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Interferon Regulatory Factor-1 / metabolism
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Interferon Regulatory Factors / genetics
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Interferon Regulatory Factors / metabolism*
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Intranuclear Inclusion Bodies / genetics
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Intranuclear Inclusion Bodies / metabolism*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Macrophages / metabolism
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Macrophages / pathology
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Male
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Mice
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Mice, Mutant Strains
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Myeloid Progenitor Cells / metabolism*
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Myeloid Progenitor Cells / pathology
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NIH 3T3 Cells
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Promyelocytic Leukemia Protein
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Protein Isoforms
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics
Substances
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Interferon Regulatory Factor-1
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Interferon Regulatory Factors
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Neoplasm Proteins
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Nuclear Proteins
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Pml protein, mouse
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Promyelocytic Leukemia Protein
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Protein Isoforms
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Proto-Oncogene Proteins
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Trans-Activators
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Transcription Factors
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Tumor Suppressor Proteins
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interferon regulatory factor-8
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proto-oncogene protein Spi-1
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PML protein, human