Journal of Biological Chemistry
Volume 284, Issue 48, 27 November 2009, Pages 33242-33254
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Transcription, Chromatin, and Epigenetics
The Interferon Consensus Sequence Binding Protein (ICSBP/IRF8) Activates Transcription of the FANCF Gene during Myeloid Differentiation*

https://doi.org/10.1074/jbc.M109.010231Get rights and content
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The interferon consensus sequence binding protein (ICSBP) is an interferon regulatory transcription factor with leukemia-suppressor activity. ICSBP regulates genes that are involved in phagocyte function, proliferation, and apoptosis. In murine models ICSBP deficiency results in a myeloproliferative disorder (MPD) with increased mature neutrophils. Over time this MPD progresses to acute myeloid leukemia (AML), suggesting that ICSBP deficiency is adequate for MPD, but additional genetic lesions are required for AML. The hypothesis of these studies is that dysregulation of key target genes predisposes to disease progression under conditions of decreased ICSBP expression. To investigate this hypothesis, we used chromatin co-immunoprecipitation to identify genes involved the ICSBP-leukemia suppressor effect. In the current studies, we identify the gene encoding Fanconi F (FANCF) as an ICSBP target gene. FancF participates in a repair of cross-linked DNA. We identify a FANCF promoter cis element, which is activated by ICSBP in differentiating myeloid cells. We also determine that DNA cross-link repair is impaired in ICSBP-deficient myeloid cells in a FancF-dependent manner. This effect is observed in differentiating cells, suggesting that ICSBP protects against the genotoxic stress of myelopoiesis. Decreased ICSBP expression is found in human AML and chronic myeloid leukemia during blast crisis (CML-BC). Our studies suggest that ICSBP deficiency may be functionally important for accumulation of chromosomal abnormalities during disease progression in these myeloid malignancies.

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*

This work was supported, in whole or in part, by National Institutes of Health Grant R01 HL 088747 (to E. A. E.). This work was also supported by a Veterans Affairs Merit Review and a Leukemia and Lymphoma Society Translational Research Award (to E. A. E.).