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An accumulation of cytogenetic and molecular genetic events characterizes the progression from MDS to secondary AML: an analysis of 38 paired samples analyzed by cytogenetics, molecular mutation analysis and SNP microarray profiling

Leukemia volume 25, pages 713–718 (2011)Cite this article

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Myelodysplastic syndromes (MDSs) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis presenting with peripheral cytopenias together with hyperplastic bone marrow. In addition, MDS patients show an increased risk of progression toward acute myeloid leukemia (AML). Although the pathogenetic mechanisms underlying both MDS and de novo AML development have broadly been studied on a genetic level, the molecular factors that determine the progression from MDS to secondary AML (s-AML) are largely unknown. So far, blast counts and cytogenetic abnormalities are known as major determinants of the risk for AML transformation,1 however, little is known about the molecular genetic events associated with MDS progression to s-AML. De novo AML is characterized by a block in differentiation as well as hyperproliferation and increased survival of a malignant clone, which is due to several genetic alterations. In comparison, the etiology of s-AML can also be regarded as a multistep process wherein similar genes might be involved. These include class I and class II mutations which are involved in signal transduction (for example, FLT3 and NRAS) and transcriptional regulation (for example, RUNX1 and MLL) as well as alterations in NPM1. Recent studies on MDS pathogenesis have reported on widespread regions of uniparental disomy (UPD) across the entire genome with frequent sites of UPD found on chromosomes 1, 4, 6, 7 and 11.2, 3, 4 Thus UPD may participate in the malignant pathological process and possibly disease progression, as accompanying loss of heterozygosity (LOH) may result in the duplication of a mutant allele located within the affected region. Comparisons of paired patient samples at both the MDS and s-AML stage provide an excellent model for studying the underlying genetic events responsible for the progression from MDS to s-AML. In the present study, we analyzed a total of 38 patients at both states of disease (male/female: 25/13; median age at diagnosis 69.5; range 29.2–82.9), who were referred to the MLL Munich Leukemia Laboratory between August 2005 and August 2009 for diagnostic workup, focusing on cytogenetic anomalies as well as molecular mutations in genes NPM1, MLL, NRAS, RUNX1 and FLT3. Additionally, we performed genome-wide SNP microarray analyses in 34 out of 38 patients at both time points. Mononuclear cells from bone marrow or peripheral blood were used for all cytogenetic, molecular and SNP array experiments.

Diagnosis was performed according to standard WHO (World Health Organization) criteria.5 Patients gave their informed written consent for this investigation and the study adheres to the rules of the local Internal Review Board and the tenets of the revised Helsinki protocol. At initial MDS diagnosis, patients were classified according to the following WHO categories: RARS (n=2), RCMD (n=3), RAEB-1 (n=11), RAEB-2 (n=9), MDS unclassifiable (n=8), CMML (n=3) and MDS/MPN overlap (n=2). Progression to s-AML was defined by blasts >20% in bone marrow or peripheral blood. Even though CMML is not classified as MDS according to the new WHO classification, this entity was still included because of the presence of myelodysplastic features and the rather high transformation rate to AML.5 AML transformation occurred at a median time of 269 days (range 40–1044 days) following initial MDS diagnosis. The high number of RAEB-1 and RAEB-2 patients (20/38; 52.6%) in our cohort reflects the fact that more advanced stages of MDS are particularly prone to s-AML progression.

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Acknowledgements

We thank all co-workers in our laboratory for their excellent technical assistance as well as all physicians for referring patient material to our center.

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  1. MLL Munich Leukemia Laboratory, Munich, Germany

    J Flach, F Dicker, S Schnittger, S Schindela, A Kohlmann, T Haferlach, W Kern & C Haferlach

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  1. J Flach
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  2. F Dicker
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Correspondence to C Haferlach.

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S Schnittger, TH, WK and CH in part own the MLL Munich Leukemia Laboratory, which offers comprehensive leukemia diagnostics. JF, S Schindela, FD and AK are employed at MLL Munich Leukemia Laboratory and declare no conflict of interest.

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Flach, J., Dicker, F., Schnittger, S. et al. An accumulation of cytogenetic and molecular genetic events characterizes the progression from MDS to secondary AML: an analysis of 38 paired samples analyzed by cytogenetics, molecular mutation analysis and SNP microarray profiling. Leukemia 25, 713–718 (2011). https://doi.org/10.1038/leu.2010.304

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