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Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
Reduced PU.1 expression causes myeloid progenitor expansion and increased leukemia penetrance in mice expressing
Matthew J Walter1, John S Park, Rhonda E Ries
1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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-RARalpha (PR) and RARalpha-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 x PU.1+/- mice developed splenomegaly because of the abnormal expansion of myeloid cells in their spleens. hCG-PR x 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 x PU.1+/+ mice (P < 0.0001). The residual PU.1 allele in hCG-PR x 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.
Insights
Reduced PU.1 transcription factor levels, combined with PML-RARalpha expression, significantly increase acute promyelocytic leukemia (APL) development in mice. This suggests a synergistic mechanism driving myeloid progenitor expansion and transformation.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- PU.1, an ETS transcription factor, is crucial for hematopoietic development.
- Haploinsufficiency of PU.1 influences myelomonocytic progenitor cell fate towards the myeloid lineage.
- Transgenic mice expressing PML-RARalpha (PR) can develop acute promyelocytic leukemia (APL) with deletions including PU.1.
Purpose of the Study:
- To investigate the direct impact of PU.1 expression levels on leukemia progression.
- To assess the synergistic effect of reduced PU.1 and PR expression in APL development.
Main Methods:
- Breeding hCG-PR mice with PU.1+/- mice to create experimental models.
- Phenotypic analysis of resulting mouse cohorts, including splenomegaly and leukemia penetrance.
- Assessing PU.1 allele expression and mutations in APL cells.
- Evaluating the effect of PR expression on PU.1 mRNA levels in cell lines and primary cells.
Main Results:
- hCG-PR x PU.1+/- mice exhibited splenomegaly due to myeloid cell expansion.
- APL disease penetrance was significantly higher (84%) in hCG-PR x PU.1+/- mice compared to controls (7%).
- PR expression reduced PU.1 mRNA levels in myeloid cells, indicating allele down-regulation.
Conclusions:
- Loss of one PU.1 copy combined with PR-induced down-regulation synergistically expands susceptible myeloid progenitors.
- This synergistic effect increases the penetrance of APL, highlighting the critical role of PU.1 levels in leukemia development.
