4th Palermo Conference on INNOVATIVE THERAPIES FOR LYMPHOID MALIGNANCIES
Published online 1 October 2009
Haematologica, Vol 94, Issue 12, 1762-1766 doi:10.3324/haematol.2009.011528
Copyright © 2009 by Ferrata Storti Foundation
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Myelodysplastic Syndromes

Clonal heterogeneity in the 5q- syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression

Martin Jädersten1, Leonie Saft2, Andrea Pellagatti3, Gudrun Göhring4, James S. Wainscoat3, Jacqueline Boultwood3, Anna Porwit2, Brigitte Schlegelberger4, Eva Hellström-Lindberg1

1 Karolinska Institutet, Department of Medicine, Division of Hematology and Center for Experimental Hematology
2 Department of Pathology, Karolinska University Hospital Stockholm Sweden
3 The LRF Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, Oxford, UK
4 The Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

Correspondence: Martin Jädersten, Karolinska Institutet, Department of Medicine, Center for Experimental Hematology, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden. E-mail: martin.jadersten{at}ki.se

Clonal heterogeneity has not been described in patients with myelodysplastic syndrome with isolated del(5q), for which lenalidomide has emerged as a highly potent treatment. However, transformation to acute myeloid leukemia is occasionally observed, particularly in patients without a cytogenetic response to lenalidomide. We performed molecular studies in a patient with classical 5q- syndrome with complete erythroid and partial cytogenetic response to lenalidomide, who evolved to high-risk myelodysplastic syndrome with complex karyotype. Immunohistochemistry of pre-treatment marrow biopsies revealed a small fraction of progenitors with overexpression of p53 and sequencing confirmed a TP53 mutation. TP53 mutated subclones have not previously been described in myelodysplastic syndrome with isolated del(5q) and indicates a previously unknown heterogeneity of this disease. The aberrant subclone remained stable during the treatment with lenalidomide and expanded at transformation, suggesting that this pre-existing cell population had molecular features which made it insensitive to lenalidomide and prone to disease progression.

Key words: resistance, del(17p), thalidomide analog.




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M. Jadersten
Pathophysiology and treatment of the myelodysplastic syndrome with isolated 5q deletion
Haematologica, March 1, 2010; 95(3): 348 - 351.
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