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

AI Article Synopsis

  • PU.1 is a crucial transcription factor for blood cell development, and its reduced expression can lead to a shift toward myeloid cell lineage, which is linked to leukemia.
  • Researchers crossed mice with a specific leukemia model (hCG-PR) with those having a reduced PU.1 gene, resulting in an increased likelihood of developing acute promyelocytic leukemia (APL).
  • The study showed that a combination of losing one PU.1 gene and decreased expression of the remaining one promotes the growth of myeloid progenitors, significantly raising the chances of leukemia progression.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1188022PMC
http://dx.doi.org/10.1073/pnas.0504247102DOI Listing

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