TP53 mutations in myelodysplastic syndromes with deletion of 5q
Author: Saft, Leonie
Date: 2013-05-24
Location: Föreläsningssalen Novum, Karolinska Universitetssjukhuset, Huddinge
Time: 09.00
Department: Inst för medicin, Huddinge / Dept of Medicine, Huddinge
Abstract
The myelodysplastic syndromes (MDS) constitute a heterogeneous group of malignant bone marrow disorders characterized by peripheral cytopenia(s) and increased risk of progression to acute myeloid leukemia (AML). International Prognostic Scoring system (IPSS) Low- or Intermediate (INT)-1 risk MDS with a deletion of 5q (del5q) were considered to have an indolent course and a low risk for progression to AML as compared to other MDS subtypes. However, more recent studies have shown that overall survival (OS) and risk for AML progression vary greatly in del(5q) MDS patients indicating that factors beyond established risk scoring systems impact patient outcome. Molecular abnormalities have emerged as putative prognostic markers.
We performed molecular studies in a patient with classical 5q-syndrome who unexpectedly evolved to high-risk MDS with complex karyotype (Paper I). Immunohistochemistry (IHC) of pre-treatment marrow biopsies revealed a small fraction of progenitors with strong p53 expression and sequencing confirmed a TP53 mutation. TP53 mutated subclones had not been described in MDS with isolated del(5q) and indicated a previously unknown heterogeneity.
In a subsequent study of 55 patients with lower-risk del(5q) MDS, 18% of the patients were found to have TP53 mutated subclones at diagnosis which rendered them at higher risk for progression (Paper II). Interestingly, the association with outcome was even stronger for p53 IHC indicating a high sensitivity of this method for early identification of patients with adverse outcome.
As a next step, we assessed p53 protein expression in a cohort of 85 lower-risk del(5q) MDS patients treated with lenalidomide within a clinical trial (Paper IV). P53 IHC positive patients showed significantly shorter overall survival, higher risk for leukemic transformation, and lower cytogenetic response rate to lenalidomide, hence validating the results from Paper II. Importantly, pyrosequencing analysis of microdissected IHC stained cells confirmed that cells with strong staining carried TP53 mutations, while moderate staining reflected wild-type TP53.
Due to the apparently exquisite sensitivity of the del(5q) clone to len, we hypothesized that higher doses of lenalidomide may induce cytogenetic and clinical responses also in patients with high-risk MDS/AML with chromosome 5 abnormalities who were refractory or ineligible for standard treatment (Paper III). In this study, we demonstrated that treatment was able to inhibit the del(5q)tumor clone in a cohort of patients with extremely advanced disease, which suggests that the selective inhibitory effect of len in vitro may be translated into a therapeutic response in vivo. Importantly, TP53 mutations were common (62%) in this cohort, and uniformly associated with treatment failure.
Altogether, our findings suggest an important role of the p53 pathway in both low- and high-risk del(5q) MDS, and in relation to treatment with lenalidomide. These findings will have major implications for risk stratification and the choice of therapy.
We performed molecular studies in a patient with classical 5q-syndrome who unexpectedly evolved to high-risk MDS with complex karyotype (Paper I). Immunohistochemistry (IHC) of pre-treatment marrow biopsies revealed a small fraction of progenitors with strong p53 expression and sequencing confirmed a TP53 mutation. TP53 mutated subclones had not been described in MDS with isolated del(5q) and indicated a previously unknown heterogeneity.
In a subsequent study of 55 patients with lower-risk del(5q) MDS, 18% of the patients were found to have TP53 mutated subclones at diagnosis which rendered them at higher risk for progression (Paper II). Interestingly, the association with outcome was even stronger for p53 IHC indicating a high sensitivity of this method for early identification of patients with adverse outcome.
As a next step, we assessed p53 protein expression in a cohort of 85 lower-risk del(5q) MDS patients treated with lenalidomide within a clinical trial (Paper IV). P53 IHC positive patients showed significantly shorter overall survival, higher risk for leukemic transformation, and lower cytogenetic response rate to lenalidomide, hence validating the results from Paper II. Importantly, pyrosequencing analysis of microdissected IHC stained cells confirmed that cells with strong staining carried TP53 mutations, while moderate staining reflected wild-type TP53.
Due to the apparently exquisite sensitivity of the del(5q) clone to len, we hypothesized that higher doses of lenalidomide may induce cytogenetic and clinical responses also in patients with high-risk MDS/AML with chromosome 5 abnormalities who were refractory or ineligible for standard treatment (Paper III). In this study, we demonstrated that treatment was able to inhibit the del(5q)tumor clone in a cohort of patients with extremely advanced disease, which suggests that the selective inhibitory effect of len in vitro may be translated into a therapeutic response in vivo. Importantly, TP53 mutations were common (62%) in this cohort, and uniformly associated with treatment failure.
Altogether, our findings suggest an important role of the p53 pathway in both low- and high-risk del(5q) MDS, and in relation to treatment with lenalidomide. These findings will have major implications for risk stratification and the choice of therapy.
List of papers:
I. Clonal heterogeneity in the 5q-syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression. Martin Jädersten, Leonie Saft, Andrea Pellagatti, Gudrun Göhring, James S. Wainscoat, Jacqueline Boultwood, Anna Porwit, Brigitte Schlegelberger, and Eva Hellström-Lindberg. Haematologica. 2009; 94(12):1762-6.
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II. TP53 Mutations in Low-Risk Myelodysplastic Syndromes with del(5q) predict disease progression. Martin Jädersten*, Leonie Saft*, Alexander Smith, Austin Kulasekararaj, Sabine Pomplun, Gudrun Göhring, Anette Hedlund, Robert Hast, Brigitte Schlegelberger, Anna Porwit, Eva Hellström-Lindberg*, and Ghulam J. Mufti*. Journal of Clinical Oncology. 2011; 29 (15): 1971-9.
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III. Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities. Lars Möllgård, Leonie Saft, Marianne Bach Treppendahl, Ingunn Dybedal, Jan Maxwell Nørgaard, Jan Astermark, Elisabeth Ejerblad, Hege Garelius, Inge Høgh Dufva, Monika Jansson, Martin Jädersten, Lars Kjeldsen, Olle Linder, Lars Nilsson, Hanne Vestergaard, Anna Porwit, Kirsten Grønbæk, and Eva Hellström-Lindberg. Haematologica. 2011; 96 (7): 963-71.
Fulltext (DOI)
Pubmed
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IV. P53 protein expression predicts outcome and cytogenetic response in patients with Low-/INT-1 risk myelodysplastic syndromes treated with lenalidomide. Leonie Saft, Mohsen Karimi, Mehran Ghaderi, András Matolscy, Ghulam Mufti, Aristoteles Giagounidis, Dominik Selleslag, Petra Muus, Guillermo Sanz, Moshe Mittelman, David Bowen, Anna Porwit, Tommy Fu, Jay Backstrom, Pierre Fenaux, Kyle J. MacBeth, and Eva Hellström-Lindberg. [Submitted]
I. Clonal heterogeneity in the 5q-syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression. Martin Jädersten, Leonie Saft, Andrea Pellagatti, Gudrun Göhring, James S. Wainscoat, Jacqueline Boultwood, Anna Porwit, Brigitte Schlegelberger, and Eva Hellström-Lindberg. Haematologica. 2009; 94(12):1762-6.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. TP53 Mutations in Low-Risk Myelodysplastic Syndromes with del(5q) predict disease progression. Martin Jädersten*, Leonie Saft*, Alexander Smith, Austin Kulasekararaj, Sabine Pomplun, Gudrun Göhring, Anette Hedlund, Robert Hast, Brigitte Schlegelberger, Anna Porwit, Eva Hellström-Lindberg*, and Ghulam J. Mufti*. Journal of Clinical Oncology. 2011; 29 (15): 1971-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities. Lars Möllgård, Leonie Saft, Marianne Bach Treppendahl, Ingunn Dybedal, Jan Maxwell Nørgaard, Jan Astermark, Elisabeth Ejerblad, Hege Garelius, Inge Høgh Dufva, Monika Jansson, Martin Jädersten, Lars Kjeldsen, Olle Linder, Lars Nilsson, Hanne Vestergaard, Anna Porwit, Kirsten Grønbæk, and Eva Hellström-Lindberg. Haematologica. 2011; 96 (7): 963-71.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. P53 protein expression predicts outcome and cytogenetic response in patients with Low-/INT-1 risk myelodysplastic syndromes treated with lenalidomide. Leonie Saft, Mohsen Karimi, Mehran Ghaderi, András Matolscy, Ghulam Mufti, Aristoteles Giagounidis, Dominik Selleslag, Petra Muus, Guillermo Sanz, Moshe Mittelman, David Bowen, Anna Porwit, Tommy Fu, Jay Backstrom, Pierre Fenaux, Kyle J. MacBeth, and Eva Hellström-Lindberg. [Submitted]
Institution: Karolinska Institutet
Supervisor: Hellström-Lindberg, Eva
Issue date: 2013-04-18
Rights:
Publication year: 2013
ISBN: 978-91-7549-137-0
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