Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13–driven mouse model
Open Access
- 11 October 2012
- journal article
- Published by American Society of Hematology in Blood
- Vol. 120 (15), 3089-3097
- https://doi.org/10.1182/blood-2012-01-405332
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.This publication has 38 references indexed in Scilit:
- p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewalGenes & Development, 2010
- Heterogeneity and hierarchy within the most primitive hematopoietic stem cell compartmentThe Journal of Experimental Medicine, 2010
- Hematopoietic stem cell: self‐renewal versus differentiationWires Systems Biology and Medicine, 2010
- Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansionProceedings of the National Academy of Sciences of the United States of America, 2010
- Distinct Hematopoietic Stem Cell Subtypes Are Differentially Regulated by TGF-β1Cell Stem Cell, 2010
- A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndromeNature Medicine, 2009
- The Tumor Suppressor p53 Regulates Polarity of Self-Renewing Divisions in Mammary Stem CellsCell, 2009
- p53 Regulates Hematopoietic Stem Cell QuiescenceCell Stem Cell, 2009
- Enrichment of hematopoietic stem cells with SLAM and LSK markers for the detection of hematopoietic stem cell function in normal and Trp53 null miceExperimental Hematology, 2008
- Identification of RPS14 as a 5q- syndrome gene by RNA interference screenNature, 2008