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Cited by 117Acute Myeloid Leukemia ResearchRetinoids in leukemia and cellular processesHematopoietic Stem Cell Transplantation

Loss of C/EBPα cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage

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Porse, Bo T., Bryder, David, Theilgaard-Mönch, Kim, Hasemann, Marie S., Anderson, Kristina, Damgaard, Inge, Jacobsen, Sten Eirik W., Nerlov, Claus·2005·The Journal of Experimental Medicine
DOI 10.1084/jem.20050067PMC PMC2212897
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Abstract

CCAAT/enhancer binding protein (C/EBP)α is a myeloid-specific transcription factor that couples lineage commitment to terminal differentiation and cell cycle arrest, and is found mutated in 9% of patients who have acute myeloid leukemia (AML). We previously showed that mutations which dissociate the ability of C/EBPα to block cell cycle progression through E2F inhibition from its function as a transcriptional activator impair the in vivo development of the neutrophil granulocyte and adipose lineages. We now show that such mutations increase the capacity of bone marrow (BM) myeloid progenitors to proliferate, and predispose mice to a granulocytic myeloproliferative disorder and transformation of the myeloid compartment of the BM. Both of these phenotypes were transplantable into lethally irradiated recipients. BM transformation was characterized by a block in granulocyte differentiation, accumulation of myeloblasts and promyelocytes, and expansion of myeloid progenitor populations—all characteristics of AML. Circulating myeloblasts and hepatic leukocyte infiltration were observed, but thrombocytopenia, anemia, and elevated leukocyte count—normally associated with AML—were absent. These results show that disrupting the cell cycle regulatory function of C/EBPα is sufficient to initiate AML-like transformation of the granulocytic lineage, but only partially the peripheral pathology of AML.

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  • This is a function common to numerous myeloid transcription factors, including Cebpa family members and Gfi1, which is itself a PU.1 target.

    “This is a function common to numerous myeloid transcription factors, including Cebpa family members and Gfi1, which is itself a PU.1 target (Hock et al., 2004; Porse et al., 2005; Pulikkan et al., 2017; Staber et al., 2013; Umek et al., 1991; Zeng et al., 2004).”

    From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Porse et al., 2005

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Authors
Porse, B. T., Bryder, D., Theilgaard-Mönch, K., Hasemann, M. S., Anderson, K., Damgaard, I., Jacobsen, S. E. W., & Nerlov, C.
Affiliations
  • Copenhagen University Hospital (DK)
  • Lund University (SE)
  • 2Granulocyte Laboratory, Copenhagen University Hospital, 2100 Copenhagen, Denmark
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2005-06-27
Volume
202
Issue
1
Pages
85-96
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20050067
PMC
PMC2212897
OpenAlex
W2126317027
Cited by
117
References
7
Citations by year
2026: 2 · 2025: 7 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 8 · 2020: 7 · 2019: 4 · 2017: 7 · 2016: 5 · 2015: 4 · 2014: 4 · 2013: 6 · 2012: 9
FWCI
5.73
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
Keywords
C/EBPα, acute myeloid leukemia, cell cycle regulation, myeloproliferative neoplasms, myeloid transformation, granulocytic differentiation, myeloblasts, transcription factor mutations, bone marrow
MeSH terms
Animals, Cell Cycle, Cell Differentiation, Cell Transformation, Neoplastic, Granulocytes, Humans, Mice, Inbred C57BL, Mice, Mutant Strains, Mutation, Myeloproliferative Disorders, Neutrophils, Phenotype, Leukemia, Myeloid, Acute, Bone Marrow Transplantation, CCAAT-Enhancer-Binding Protein-alpha, Myeloid Progenitor Cells, Cell Proliferation, Mice

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