p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)
Leonie Saft, Mohsen Karimi, Mehran Ghaderi, András 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, Leonie Saft, Mohsen Karimi, Mehran Ghaderi, András 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
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).
Copyright© Ferrata Storti Foundation.
Figures
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Figure 4.
Probability of AML progression by…
Figure 4.
Probability of AML progression by the presence of
Figure 5.
Increase of p53 in eight…
Figure 5.
Increase of p53 in eight of 21 patients after 3 months, and in…
- Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities.Möllgård L, Saft L, Treppendahl MB, Dybedal I, Nørgaard JM, Astermark J, Ejerblad E, Garelius H, Dufva IH, Jansson M, Jädersten M, Kjeldsen L, Linder O, Nilsson L, Vestergaard H, Porwit A, Grønbæk K, Hellström-Lindberg E. Möllgård L, et al. Haematologica. 2011 Jul;96(7):963-71. doi: 10.3324/haematol.2010.039669. Haematologica. 2011. PMID: 21719884 Free PMC article. Clinical Trial.
- Lenalidomide in patients with red blood cell transfusion-dependent myelodysplastic syndrome and del(5q): a single-centre "real-world" experience.Cerqui E, Pelizzari A, Schieppati F, Borlenghi E, Pagani C, Bellotti D, Lamorgese C, Boiocchi L, Sottini A, Imberti L, Rossi G. Cerqui E, et al. Leuk Lymphoma. 2015;56(11):3129-34. doi: 10.3109/10428194.2015.1034703. Epub 2015 May 12. Leuk Lymphoma. 2015. PMID: 25811676
- Therapeutic Outcomes and Prognostic Impact of Gene Mutations Including TP53 and SF3B1 in Patients with Del(5q) Myelodysplastic Syndromes (MDS).Chan O, Ali NA, Sallman D, Padron E, Lancet J, Komrokji R. Chan O, et al. Clin Lymphoma Myeloma Leuk. 2022 Jul;22(7):e467-e476. doi: 10.1016/j.clml.2022.01.002. Epub 2022 Jan 10. Clin Lymphoma Myeloma Leuk. 2022. PMID: 35101379
- TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression.Jädersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Göhring G, Hedlund A, Hast R, Schlegelberger B, Porwit A, Hellström-Lindberg E, Mufti GJ. Jädersten M, et al. J Clin Oncol. 2011 May 20;29(15):1971-9. doi: 10.1200/JCO.2010.31.8576. Epub 2011 Apr 25. J Clin Oncol. 2011. PMID: 21519010
- Lenalidomide as a disease-modifying agent in patients with del(5q) myelodysplastic syndromes: linking mechanism of action to clinical outcomes.Giagounidis A, Mufti GJ, Fenaux P, Germing U, List A, MacBeth KJ. Giagounidis A, et al. Ann Hematol. 2014 Jan;93(1):1-11. doi: 10.1007/s00277-013-1863-5. Epub 2013 Sep 10. Ann Hematol. 2014. PMID: 24018623 Free PMC article. Review.
- Synonymous Variants: Necessary Nuance in Our Understanding of Cancer Drivers and Treatment Outcomes.Kaissarian NM, Meyer D, Kimchi-Sarfaty C. Kaissarian NM, et al. J Natl Cancer Inst. 2022 Aug 8;114(8):1072-1094. doi: 10.1093/jnci/djac090. J Natl Cancer Inst. 2022. PMID: 35477782 Review.
- Pseudo-mutant P53 is a unique phenotype of DNMT3A-mutated pre-leukemia.Tuval A, Brilon Y, Azogy H, Moskovitz Y, Leshkowitz D, Salame TM, Minden MD, Tal P, Rotter V, Oren M, Kaushansky N, Shlush LI. Tuval A, et al. Haematologica. 2022 Nov 1;107(11):2548-2561. doi: 10.3324/haematol.2021.280329. Haematologica. 2022. PMID: 35199506 Free PMC article.
- TP53 in Myelodysplastic Syndromes.Jiang Y, Gao SJ, Soubise B, Douet-Guilbert N, Liu ZL, Troadec MB. Jiang Y, et al. Cancers (Basel). 2021 Oct 27;13(21):5392. doi: 10.3390/cancers13215392. Cancers (Basel). 2021. PMID: 34771553 Free PMC article. Review.
- Accuracy of bone marrow histochemical TP53 expression compared to the detection of TP53 somatic mutations in patients with myelodysplastic syndromes harbouring a del5q cytogenetic abnormality.Oliva EN, Latagliata R, Sabattini E, Mammì C, Cuzzola M, D'Errigo MG, Cannatà MC, Bova I, Capodanno I, Palumbo GA, Pane F, Reda G, Fianchi L, Riva M, Poloni A. Oliva EN, et al. Am J Blood Res. 2021 Aug 15;11(4):417-426. eCollection 2021. Am J Blood Res. 2021. PMID: 34540351 Free PMC article.
- Single Cell Detection of the p53 Protein by Mass Cytometry.Fagerholt OHE, Hellesøy M, Gullaksen SE, Gjertsen BT. Fagerholt OHE, et al. Cancers (Basel). 2020 Dec 9;12(12):3699. doi: 10.3390/cancers12123699. Cancers (Basel). 2020. PMID: 33317179 Free PMC article.
- Research Support, Non-U.S. Gov't
- Antineoplastic Combined Chemotherapy Protocols / therapeutic use
- Bone Marrow / metabolism
- Bone Marrow / pathology
- Chromosome Deletion*
- Chromosomes, Human, Pair 5*
- Disease Progression
- Gene Expression*
- Humans
- Immunohistochemistry
- Leukemia, Myeloid, Acute
- Mutation
- Myelodysplastic Syndromes / diagnosis
- Myelodysplastic Syndromes / drug therapy
- Myelodysplastic Syndromes / genetics*
- Myelodysplastic Syndromes / mortality
- Patient Outcome Assessment
- Prognosis
- Reproducibility of Results
- Treatment Outcome
- Tumor Suppressor Protein p53 / genetics*
- Tumor Suppressor Protein p53 / metabolism
- Tumor Suppressor Protein p53
- ClinicalTrials.gov/NCT00179621
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
![Figure 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4040908/bin/991041.fig4.jpg)
Figure 5.
Increase of p53 in eight…
Figure 5.
Increase of p53 in eight of 21 patients after 3 months, and in…
![Figure 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4040908/bin/991041.fig5.jpg)
Source: PubMed