Role of p21 in a Mouse Model of NUP98-HOXD13 Fusion Driven Myelodysplastic Syndromes (MDS)

The myelodysplastic syndromes (MDS) are clonal stem cell disorders, characterized by ineffective hematopoiesis leading to cytopenias and a high rate of progression to acute myeloid leukemia (AML). The NUP98-HOXD13 (NHD13) fusion has been found in patients with MDS and AML. A transgenic (Tg) mouse model, generated by Peter Aplan’s group, which utilizes Vav 1 regulatory elements to direct expression of the NHD13 transgene in hematopoietic tissues, displays the phenotypic features of MDS including a chronic phase of cytopenias followed by transformation to AML (Lin et al., 2005). We previously reported that loss of one or both alleles of p53 did not rescue the MDS phenotype in NHD13+ Tg mice, but rather exacerbated the MDS phenotype and accelerated the development of AML (Xu et al., 2012). Expression of p21WAF1/CIP1(p21) was increased in the Lin−Sca-1+c-Kit+ (LSK) cells isolated from NHD13+ Tg mice, so we generated and analyzed NHD13+p21+/– and NHD13+p21–/– mice to further investigate whether the accelerated MDS and AML that occurs in the absence of p53 relates to the defective expression of the p53 target gene. Deletion of p21 significantly altered the fate of the NHD13+ Tg mice. All of the NHD13+p21–/– mice died of AML, rather than MDS. Only 18% (4 out of total 22 mice) of the NHD13+p21+/– mice developed MDS with a median survival of 289 d; in contrast 31% (9 out of total 29 mice) of NHD13+ Tg mice died from MDS, with a median survival of 230 d (p Disclosures Armstrong: Epizyme : Consultancy.