Clinical significance of genetic aberrations in secondary acute myeloid leukemia

Jelena D. Milosevic, Ana Puda, Luca Malcovati, Tiina Berg, Michael Hofbauer, Alexey Stukalov, Thorsten Klampfl, Ashot S. Harutyunyan, Heinz Gisslinger, Bettina Gisslinger, Tatiana Burjanivova, Elisa Rumi, Daniela Pietra, Chiara Elena, Alessandro M. Vannucchi, Michael Doubek, Dana Dvorakova, Blanka Robesova, Rotraud Wieser, Elisabeth KollerNada Suvajdzic, Dragica Tomin, Natasa Tosic, Jacques Colinge, Zdenek Racil, Michael Steurer, Sonja Pavlovic, Mario Cazzola, Robert Kralovics

Research output: Contribution to journalArticle

Abstract

The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% ± 9.4% vs. 35.4% ± 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.33-5.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms.

Original languageEnglish
Pages (from-to)1010-1016
Number of pages7
JournalAmerican Journal of Hematology
Volume87
Issue number11
DOIs
Publication statusPublished - Nov 2012

ASJC Scopus subject areas

  • Hematology

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    Milosevic, J. D., Puda, A., Malcovati, L., Berg, T., Hofbauer, M., Stukalov, A., Klampfl, T., Harutyunyan, A. S., Gisslinger, H., Gisslinger, B., Burjanivova, T., Rumi, E., Pietra, D., Elena, C., Vannucchi, A. M., Doubek, M., Dvorakova, D., Robesova, B., Wieser, R., ... Kralovics, R. (2012). Clinical significance of genetic aberrations in secondary acute myeloid leukemia. American Journal of Hematology, 87(11), 1010-1016. https://doi.org/10.1002/ajh.23309