Lack of IRF-1 expression in acute promyelocytic leukemia and in a subset of acute myeloid leukemias with del(5)(q31)

Green, W B; Slovak, Marilyn L.; Chen, I M; Pallavicini, Maria G.; Hecht, Jochen; Willman, Cheryl L.

doi:10.1038/sj.leu.2401596

Cited by 54 publications

(45 citation statements)

References 34 publications

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“…In addition, PU.1 mutations have been observed in some AML patients (49). The importance of IRF-1 in myeloid cell differentiation is highlighted because of its functional inactivation in various neoplastic disorders such as accelerated exon skipping in CML (50) and deletions in AML and myelodysplasias (51). IRF-8 is also a myeloid commitment factor.…”

Section: Discussionmentioning

confidence: 99%

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

Dror

Rave-Harel

Burchert

et al. 2007

Journal of Biological Chemistry

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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.

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Section: Discussionmentioning

confidence: 99%

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

Dror

Rave-Harel

Burchert

et al. 2007

Journal of Biological Chemistry

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“…The human IRF-1 gene was mapped to chromosome 5q31.1 and loss of heterozygosity in this region is frequent in leukemias, preleukemic myelodysplastic syndrome (MDS) Green et al, 1999) and gastric cancer (Tamura et al, 1996). IRF-1 function can be abrogated by mutation (Nozawa et al, 1998), exon skipping (Harada et al, 1994) and by binding of the protein product to nucleophosmin, a putative nucleosome assembly factor (Kondo et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

The class II tumour suppressor gene H-REV107-1 is a target of interferon-regulatory factor-1 and is involved in IFNγ-induced cell death in human ovarian carcinoma cells

et al. 2002

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“…In addition to the anti-viral response, these include: regulation of the cell cycle YuLee, 1992, 1994) and apoptosis (Kirchhoff and Hauser, 1999;Tamura et al, 1995); development of the T cell immune response (Matsuyama et al, 1993); susceptibility to transformation by oncogenes , and the response to genotoxic agents (Prost et al, 1998;Tanaka et al, 1996). Furthermore, deletion or point mutation of the IRF-1 gene (Eason et al, 1999;Willman et al, 1993), and exon skipping of IRF-1 mRNA have been linked to the development of human haemopoietic malignancies, such as leukaemia and myelodysplastic syndrome (Boultwood et al, 1993;Green et al, 1999;Willman et al, 1993), as well as, solid phase tumours of the gastro-intestinal tract Tamura et al, 1996). In conjunction with a recent study showing that IRF-1 can modulate tumour susceptibility in the presence of oncogenic lesions (Nozawa et al, 1999), the above research provides evidence that IRF-1 has tumour suppressor/modifier activity.…”

Section: Introductionmentioning

confidence: 99%

Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway

et al. 2002

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The mechanism by which genotoxic stress induces IRF-1 and the signalling components upstream of this antioncogenic transcription factor during the response to DNA damage are not known. We demonstrate that IRF-1 and the tumour suppressor protein p53 are coordinately up-regulated during the response to DNA damage in an ATM-dependent manner. Induction of IRF-1 protein by either ionizing radiation (IR) or etoposide occurs through a concerted mechanism involving increased IRF-1 expression/synthesis and an increase in the half-life of the IRF-1 protein. A striking defect in the induction of both IRF-1 mRNA and IRF-1 protein was observed in ATM deficient cells. Although ATM deficient cells failed to increase IRF-1 in response to genotoxic stress, the induction of IRF-1 in response to viral mimetics remained intact. Re-expression of the ATM kinase in AT cells restored the DNA damage inducibility of IRF-1, whilst the PI-3 kinase inhibitor wortmannin inhibited IRF-1 induction by DNA damage in ATM-positive cells. The data highlight a role for the ATM kinase in orchestrating the coordinated induction and transcriptional cooperation of IRF-1 and p53 to regulate p21 expression. Thus, IRF-1 is controlled by two distinct signalling pathways; a JAK/STAT-signalling pathway in viral infected cells and an ATM-signalling pathway in DNA damaged cells.

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Lack of IRF-1 expression in acute promyelocytic leukemia and in a subset of acute myeloid leukemias with del(5)(q31)

Cited by 54 publications

References 34 publications

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

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

The class II tumour suppressor gene H-REV107-1 is a target of interferon-regulatory factor-1 and is involved in IFNγ-induced cell death in human ovarian carcinoma cells

Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway

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