Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13-driven mouse model

Haiming Xu, Silvia Menendez, Brigitte Schlegelberger, Narae Bae, Peter D. Aplan, Gudrun Göhring, Tony R. Deblasio, Stephen D. Nimer

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

The nucleoporin gene NUP98 is fused to several genes including HOXD13 in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia, and chronic myeloid leukemia, blast crisis. Genetically engineered mice that express a NUP98-HOXD13 (NHD13) transgene (Tg) display the phenotypic features of MDS, including cytopenias, bone marrow dysplasia, and transformation to acute leukemia. Here we show that short-term treatment with the p53 inhibitor Pifithrin-α partially and transiently rescued the myeloid and lymphoid abnormalities found in NHD13+ Tg mice, with no improvement in the anemia, while the genetic deletion of 2 alleles of p53 rescued both the myeloid progenitor cell and long-term hematopoietic stem cell compartments. Nonetheless, loss of one or both alleles of p53 did not rescue the MDS phenotype, but instead exacerbated the MDS phenotype and accelerated the development of acute myeloid leukemia. Our studies suggest that while targeting p53 may transiently improve hematopoiesis in MDS, over the long-term, it has detrimental effects, raising caution about abrogating its function to treat the cytopenias that accompany this disease.

Original languageEnglish (US)
Pages (from-to)3089-3097
Number of pages9
JournalBlood
Volume120
Issue number15
DOIs
StatePublished - Oct 11 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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