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Case Reports
. 2009 Dec;94(12):1762-6.
doi: 10.3324/haematol.2009.011528. Epub 2009 Oct 1.

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

Martin Jädersten  1 , Leonie Saft, Andrea Pellagatti, Gudrun Göhring, James S Wainscoat, Jacqueline Boultwood, Anna Porwit, Brigitte Schlegelberger, Eva Hellström-Lindberg
Affiliations
Case Reports

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

Martin Jädersten et al. Haematologica. 2009 Dec.

Abstract

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.

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Figures

Figure 1.
Figure 1.
(A) Karyogram of a metaphase at time of progression shown by M-FISH. (B) Partial karyograms of the structural aberrant chromosomes 11, 16 and 17 shown in detail. After M-FISH the additional chromosomal material in the short arm of the derivative chromosome 11 could be identified as material of chromosome 16: der(11)t(11;16)(p11;?). The additional chromosomal material in the long arm of the derivative chromosome 16 and the additional material in the short arm of the derivative chromosome 17 were identified as material of chromosome 11: der(16)t(11;16)(q12;q12) and der(11;17)(p10;q10). Immunohistochemistry demonstrated (C) a population aberrantly over-expressing p53 already pre-treatment, and (D) a clear increase of this population at disease progression.
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