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 (

PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia

“…Similar to the previous study, 18 we observed a shortened lifespan in NHD13 mice lacking p53, with a median survival of 95 days compared with 126 days in p53-deficient mice alone (Po0.01) and 353 days in NHD13 mice alone Distinct roles for P53 and PUMA in myelodysplasia AA Guirguis et al…”

“…17 To define the hematopoietic subsets affected by apoptosis in NHD13 mice, we measured the numbers and percentages of cells undergoing apoptosis among defined hematopoietic stem and progenitor cells by flow cytometry. As previously reported, 18,19 the proportions of Lineage neg Sca-1 + c-Kit + (LSK) stem/multi-potent progenitor cells and Lineage neg Sca-1 − c-Kit + (LK) progenitor cells were reduced approximately three-fold and two-fold, respectively (Figure 1a). Using the Signaling Lymphocyte Activation Molecules (SLAM) CD48 and CD150, we found that longterm (LT)-HSCs (LSK,CD150 + CD48 − ) and short-term (ST)-HSCs (LSK, CD150 − CD48 − ) were more markedly reduced (410-fold) in proportion and absolute numbers than multipotent progenitors, MPP (LSKCD150 − CD48 + ) (Figures 1a and b).…”

“…This was somewhat different from the previous report where absence of p53 rescued LT-HSC numbers. 18 Nevertheless, in our hands, this selective rescue of MPPs but not LT-HSCs was not specific for loss of p53 alone because enforced expression of BCL-2 had a similar effect (Figure 3b). Importantly, the rescue of MPPs by the absence of p53 was associated with reduced apoptosis (Figure 3c).…”

“…13 Consistent with this, it has been reported that loss of p53 accelerated leukemic transformation in NHD13 mice although the impact of p53 loss on apoptosis of hematopoietic cells was not directly examined. 18 Examination of MPP (the predominant LSK sub-population) for activation of p53 revealed a twofold increase in the total and the Ser18 phosphorylated form of p53 (Figure 2a). Gene expression profiling of the LSK population (which comprises 90% MPP) revealed increased expression of Noxa, a direct transcriptional target of p53, but not the other major pro-apoptotic BH3-only target Puma (Figure 2b).…”

“…Additionally, prevention of disease progression contrasts with the absence of p53 in the NHD13 mouse model, which is thought to prevent apoptosis (although not directly examined) yet was reported to promote disease progression. 18 To address these caveats, we have used knockout mice of p53 and its transcriptional pro-apoptotic targets Noxa and Puma to clarify the relationship between apoptosis and progression of MDS to AML. …”