p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)

Leonie Saft, Mohsen Karimi, Mehran Ghaderi, A. Matolcsy, Ghulam J. Mufti, Austin Kulasekararaj, Gudrun Göhring, Aristoteles Giagounidis, Dominik Selleslag, Petra Muus, Guillermo Sanz, Moshe Mittelman, David Bowen, Anna Porwit, Tommy Fu, Jay Backstrom, Pierre Fenaux, Kyle J. MacBeth, Eva Hellström-Lindberg

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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).

Original languageEnglish
Pages (from-to)1041-1049
Number of pages9
JournalHaematologica
Volume99
Issue number6
DOIs
Publication statusPublished - Jun 1 2014

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Myelodysplastic Syndromes
Immunohistochemistry
Proteins
Acute Myeloid Leukemia
High-Throughput Nucleotide Sequencing
Cytogenetics
Bone Marrow Cells
Lasers
Stem Cells
Multivariate Analysis
Bone Marrow
Clinical Trials
Technology
Biopsy
Mutation
Survival
Chromosome 5q Deletion Syndrome
MDS 004

ASJC Scopus subject areas

  • Hematology
  • Medicine(all)

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p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q). / Saft, Leonie; Karimi, Mohsen; Ghaderi, Mehran; Matolcsy, A.; Mufti, Ghulam J.; Kulasekararaj, Austin; Göhring, Gudrun; Giagounidis, Aristoteles; Selleslag, Dominik; Muus, Petra; Sanz, Guillermo; Mittelman, Moshe; Bowen, David; Porwit, Anna; Fu, Tommy; Backstrom, Jay; Fenaux, Pierre; MacBeth, Kyle J.; Hellström-Lindberg, Eva.

In: Haematologica, Vol. 99, No. 6, 01.06.2014, p. 1041-1049.

Research output: Contribution to journalArticle

Saft, L, Karimi, M, Ghaderi, M, Matolcsy, A, Mufti, GJ, Kulasekararaj, A, Göhring, G, Giagounidis, A, Selleslag, D, Muus, P, Sanz, G, Mittelman, M, Bowen, D, Porwit, A, Fu, T, Backstrom, J, Fenaux, P, MacBeth, KJ & Hellström-Lindberg, E 2014, 'p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)', Haematologica, vol. 99, no. 6, pp. 1041-1049. https://doi.org/10.3324/haematol.2013.098103
Saft, Leonie ; Karimi, Mohsen ; Ghaderi, Mehran ; Matolcsy, A. ; Mufti, Ghulam J. ; Kulasekararaj, Austin ; Göhring, Gudrun ; Giagounidis, Aristoteles ; Selleslag, Dominik ; Muus, Petra ; Sanz, Guillermo ; Mittelman, Moshe ; Bowen, David ; Porwit, Anna ; Fu, Tommy ; Backstrom, Jay ; Fenaux, Pierre ; MacBeth, Kyle J. ; Hellström-Lindberg, Eva. / p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q). In: Haematologica. 2014 ; Vol. 99, No. 6. pp. 1041-1049.
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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).",
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AU - Saft, Leonie

AU - Karimi, Mohsen

AU - Ghaderi, Mehran

AU - Matolcsy, A.

AU - Mufti, Ghulam J.

AU - Kulasekararaj, Austin

AU - Göhring, Gudrun

AU - Giagounidis, Aristoteles

AU - Selleslag, Dominik

AU - Muus, Petra

AU - Sanz, Guillermo

AU - Mittelman, Moshe

AU - Bowen, David

AU - Porwit, Anna

AU - Fu, Tommy

AU - Backstrom, Jay

AU - Fenaux, Pierre

AU - MacBeth, Kyle J.

AU - Hellström-Lindberg, Eva

PY - 2014/6/1

Y1 - 2014/6/1

N2 - 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).

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