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. 2014 Jun;99(6):1041-9.
doi: 10.3324/haematol.2013.098103. Epub 2014 Mar 28.

p53 Protein Expression Independently Predicts Outcome in Patients With Lower-Risk Myelodysplastic Syndromes With del(5q)

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p53 Protein Expression Independently Predicts Outcome in Patients With Lower-Risk Myelodysplastic Syndromes With del(5q)

Leonie Saft et al. Haematologica. .
Free PMC article

Abstract

Del(5q) myelodysplastic syndromes defined by the International Prognostic Scoring System as low- or intermediate-1-risk (lower-risk) are considered to have an indolent course; however, recent data have identified a subgroup of these patients with more aggressive disease and poorer outcomes. Using deep sequencing technology, we previously demonstrated that 18% of patients with lower-risk del(5q) myelodysplastic syndromes carry TP53 mutated subclones rendering them at higher risk of progression. In this study, bone marrow biopsies from 85 patients treated with lenalidomide in the MDS-004 clinical trial were retrospectively assessed for p53 expression by immunohistochemistry in association with outcome. Strong p53 expression in ≥ 1% of bone marrow progenitor cells, observed in 35% (30 of 85) of patients, was significantly associated with higher acute myeloid leukemia risk (P=0.0006), shorter overall survival (P=0.0175), and a lower cytogenetic response rate (P=0.009), but not with achievement or duration of 26-week transfusion independence response. In a multivariate analysis, p53-positive immunohistochemistry was the strongest independent predictor of transformation to acute myeloid leukemia (P=0.0035). Pyrosequencing analysis of laser-microdissected cells with strong p53 expression confirmed the TP53 mutation, whereas cells with moderate expression predominantly had wild-type p53. This study validates p53 immunohistochemistry as a strong and clinically useful predictive tool in patients with lower-risk del(5q) myelodysplastic syndromes. This study was based on data from the MDS 004 trial (clinicaltrials.gov identifier: NCT00179621).

Figures

Figure 1.
Figure 1.
The p53-DO1 stain shows cells with moderate (2+) and strong (3+) nuclear staining (top). The lower left panel shows a BM sample with only scattered strong p53-positive staining (red circle) around the 1% level by both manual and automated image assessment. The lower right panel shows a BM sample with the presence of scattered weak (1+; yellow circle) and moderate (2+; orange circle) p53-positive staining cells, but no cells with strong (3+) nuclear staining.
Figure 2.
Figure 2.
Laser-microdissection of BM cells with strong (3+; red circle), moderate (2+; orange circle), and negative p53-staining collected in three separate tubes from the same formalin fixed, paraffin-embedded BM sample (patient 34, BM sample at 105 months from initial diagnosis). TP53 mutation analysis by pyrosequencing using DNA from microdissected cells. The images were taken with a Leica Laser Microscope at 60× magnification before (left) and after (right) laser-microdissection; p53-negative microdissected cells are not shown in the upper images. Patient 34 had classical 5q- syndrome [46, XX, del(5q)] with a previously known C275F (G>T) TP53 mutation.
Figure 3.
Figure 3.
Overall survival by the presence of <1% (p53-negative) and =1% (p53-positive) BM progenitor cells with strong (3+) p53 staining.
Figure 4.
Figure 4.
Probability of AML progression by the presence of <1% (p53-negative) and =1% (p53-positive) BM progenitor cells with strong (3+) p53 staining.
Figure 5.
Figure 5.
Increase of p53 in eight of 21 patients after 3 months, and in one patient (patient 5) after 12 months. Patients 5, 6, 9, and 17 had cytogenetic evolution with complex karyotypes at 12, 22, 6, and 3 months, respectively. The decrease in p53 in the last sample in patient 8 may reflect very low BM cellularity (10%). The histology panels show p53-DO1 staining in BM samples from Patient 5 at screening (upper right) and after 12 months (lower left) at 20×/40× magnification. Cells with strong (3+) p53 expression were negative for CD34 (lower middle) and positive for hemoglobin (lower right). No increase in CD34+ cells was seen, but aberrant expression of CD34 in megakaryocytes was noted.

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