Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13-driven mouse model Journal Article
| Authors: | Xu, H.; Menendez, S.; Schlegelberger, B.; Bae, N.; Aplan, P. D.; Göhring, G.; Deblasio, T. R.; Nimer, S. D. |
| Article Title: | Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13-driven mouse model |
| 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. |
| Keywords: | controlled study; survival rate; acute granulocytic leukemia; gene deletion; leukemia, myeloid, acute; nonhuman; flow cytometry; animal cell; mouse; phenotype; animals; mice; mice, knockout; allele; animal tissue; gene; anemia; animal experiment; animal model; protein p53; mice, inbred c57bl; mice, transgenic; cell transformation, neoplastic; myelodysplastic syndrome; oncogene proteins, fusion; hematopoietic stem cells; tumor suppressor protein p53; hematopoiesis; hematopoietic stem cell; disease models, animal; cytopenia; disease exacerbation; myeloid progenitor cell; myelodysplastic syndromes; nucleoporin 98; haploinsufficiency; toluene; pifithrin alpha; hoxd13 gene; benzothiazoles |
| Journal Title: | Blood |
| Volume: | 120 |
| Issue: | 15 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2012-10-11 |
| Start Page: | 3089 |
| End Page: | 3097 |
| Language: | English |
| DOI: | 10.1182/blood-2012-01-405332 |
| PROVIDER: | scopus |
| PMCID: | PMC3471517 |
| PUBMED: | 22927245 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 December 2012" - "CODEN: BLOOA" - "Source: Scopus" |
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