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Cited by 58Acute Myeloid Leukemia Researchinterferon and immune responsesGenomics and Chromatin Dynamics

The interferon regulatory factor ICSBP/IRF-8 in combination with PU.1 up-regulates expression of tumor suppressor p15Ink4b in murine myeloid cells

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Schmidt, Martina, Bies, Juraj, Tamura, Tomohiko, Ozato, Keiko, Wolff, Linda·2004·Blood
DOI 10.1182/blood-2003-01-0285
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Abstract

CDKN2B (INK4B), which encodes the cyclin-dependent kinase inhibitor p15INK4b, is up-regulated by many cytokines found in hematopoietic environments in vivo. In human acute myeloid leukemias (AMLs), it is inactivated with high frequency. To gain insight into the regulatory pathways leading to the normal activation of p15Ink4b expression, we examined interferon β (IFNβ)–induced transcription. Using reporter gene assays in murine myeloid cells M1, we determined that a 328-bp fragment, located 117 to 443 bp upstream of the translation initiation site, was sufficient to activate transcription. Both the interferon consensus sequence-binding protein/interferon regulatory factor 8 (ICSBP/IRF-8) and PU.1 were able to increase transcription from this region. It was determined that both ICSBP and PU.1 must bind to DNA to form a stable PU.1/ICSBP binding complex. Interestingly, introduction of the ICSBP into ICSBP-null Tot2 cells led to a significant increase in p15Ink4b RNA expression. This regulation of the Ink4b promoter is apparently myeloid specific because both ICSBP and PU.1 are myeloid commitment factors. Importantly, this provides a mechanism to explain in part the tumor suppressor activity of ICSBP, since ICSBP-deficient mice develop a chronic myelogenous leukemia (CML)–like disease and a high percentage of human AML and CML lack ICSBP transcripts.

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  • In various cell types PU.1 induces expression of TRAIL and Ink4b, which respectively induce apoptosis and inhibit cell proliferation.

    “In various cell types PU.1 has also been shown to induce expression of TRAIL and Ink4b, which respectively induce apoptosis and inhibit cell proliferation [28], [29].”

    From The Transcription Factor PU.1 Regulates γδ T Cell Homeostasis (2011) · cites this paper as [29]

    The Discussion reports that PU.1 and ICSBP regulate p15 Ink4b expression in IFNβ-treated myeloid cells, and the Introduction identifies p15 Ink4b as a cell-cycle inhibitor. This supports the Ink4b portion for this source, but not the broader implication that PU.1 induces it across various cell types or independently of ICSBP. The separate TRAIL claim appears to be assigned to the other citation. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Irf8 cooperatively regulates the expression of target genes together with PU.1.

    “As Irf8 cooperatively regulates the expression of target genes together with PU.130–32”

    From Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia (2015) · cites this paper as [30]

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Cited by

Sorted by citations

Authors
Schmidt, M., Bies, J., Tamura, T., Ozato, K., & Wolff, L.
Affiliations
National Institutes of Health (US)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2004-06-01
Volume
103
Issue
11
Pages
4142-4149
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2003-01-0285
OpenAlex
W2059557201
Cited by
58
References
10
Citations by year
2025: 2 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2017: 1 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 5 · 2012: 2
FWCI
2.51
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Cancer Research Institute
  • Slovenská Akadémia Vied
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
PU.1, CDKN2B, transcriptional regulation, myeloid cells, acute myeloid leukemia, chronic myeloid leukemia, tumor suppressor
MeSH terms
Interferon Regulatory Factor-8, Proto-Oncogene Protein Spi-1, Acute Disease, Animals, Antineoplastic Agents, Base Sequence, Gene Expression Regulation, Hematopoietic Stem Cells, Leukemia, Myeloid, Molecular Sequence Data, Promoter Regions, Genetic, Proto-Oncogene Proteins, Repressor Proteins, Transcription, Genetic, Trans-Activators, Up-Regulation, Interferon-beta, Gene Deletion, Cell Cycle Proteins, Myeloid Cells, Tumor Suppressor Proteins, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p15, Interferon Regulatory Factors, Mice

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