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Cited by 83Retinoids in leukemia and cellular processesAcute Myeloid Leukemia ResearchGenomics and Chromatin Dynamics

Reduced PU.1 expression causes myeloid progenitor expansion and increased leukemia penetrance in mice expressing PML-RARα

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Walter, Matthew J., Park, John S., Ries, Rhonda E., Lau, Steven K. M., McLellan, Michael, Jaeger, Sara, Wilson, Richard K., Mardis, Elaine R. +1 more·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0504247102PMC PMC1188022
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Abstract

PU.1 is a member of the ETS family of transcription factors that is known to be important for hematopoietic development. Recently, haploinsufficiency for PU.1 has been shown to cause a shift in myelomonocytic progenitor fate toward the myeloid lineage. We have previously shown that transgenic mice expressing PML-RARα (PR) and RARα-PML frequently develop acute promyelocytic leukemia (APL) in association with a large (>20 Mb) interstitial deletion of chromosome 2 that includes PU.1 . To directly assess the relevance of levels of expression of PU.1 for leukemia progression, we bred hCG-PR mice with PU.1 +/- mice and assessed their phenotype. Young, nonleukemic hCG-PR × PU.1 +/- mice developed splenomegaly because of the abnormal expansion of myeloid cells in their spleens. hCG-PR × PU.1 +/- mice developed a typical APL syndrome after a long latent period, but the penetrance of disease was 84%, compared with 7% in hCG-PR × PU.1 +/+ mice ( P < 0.0001). The residual PU.1 allele in hCG-PR × PU.1 +/- APL cells was expressed, and complete exonic resequencing revealed no detectable mutations in nine of nine samples. However, PR expression in U937 myelomonocytic cells and primary murine myeloid bone marrow cells caused a reduction in PU.1 mRNA levels. Therefore, the loss of one copy of PU.1 through a deletional mechanism, plus down-regulation of the residual allele caused by PR expression, may synergize to expand the pool of myeloid progenitors that are susceptible to transformation, increasing the penetrance of APL.

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Cited by

Sorted by citations

Authors
Walter, M. J., Park, J. S., Ries, R. E., Lau, S. K. M., McLellan, M., Jaeger, S., Wilson, R. K., Mardis, E. R., & Ley, T. J.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Ley, Timothy J.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-08-19
Volume
102
Issue
35
Pages
12513-12518
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0504247102
PMC
PMC1188022
OpenAlex
W2120102447
Cited by
83
References
1
Citations by year
2024: 1 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 2 · 2017: 3 · 2016: 1 · 2015: 5 · 2014: 6 · 2013: 6 · 2012: 5
FWCI
3.15
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Leukemia Research Foundation
  • Alvin J. Siteman Cancer Center
  • National Institutes of Health
  • National Cancer Institute (R01CA083962, CA101937, CA83962, P01CA101937)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
PU.1, PML-RARα, acute promyelocytic leukemia, haploinsufficiency, ETS transcription factors, chromosome 2 deletion, splenomegaly, myelomonocytic cells, transgenic mice
MeSH terms
Proto-Oncogene Protein Spi-1, Animals, Chromosome Deletion, Humans, Mice, Inbred C57BL, Mice, Transgenic, Neoplasm Proteins, Phenotype, Proto-Oncogene Proteins, RNA, Messenger, RNA, Neoplasm, Splenomegaly, Leukemia, Promyelocytic, Acute, Oncogene Proteins, Fusion, Trans-Activators, Down-Regulation, Gene Expression, U937 Cells, Myeloid Progenitor Cells, Mice

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