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Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia

Krönke, Jan ; Bullinger, Lars ; Teleanu, Veronica ; Tschürtz, Florian ; Gaidzik, Verena I. ; Kühn, Michael W.M. ; Rücker, Frank G. ; Holzmann, Karlheinz ; Paschka, Peter ; Kapp-Schwörer, Silke ; Späth, Daniela ; Kindler, Thomas ; Schittenhelm, Marcus ; Krauter, Jürgen ; Ganser, Arnold ; Göhring, Gudrun ; Schlegelberger, Brigitte ; Schlenk, Richard F. ; Döhner, Hartmut ; Döhner, Konstanze

Blood, 2013-07, Vol.122 (1), p.100-108 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia
Autor: Krönke, Jan ; Bullinger, Lars ; Teleanu, Veronica ; Tschürtz, Florian ; Gaidzik, Verena I. ; Kühn, Michael W.M. ; Rücker, Frank G. ; Holzmann, Karlheinz ; Paschka, Peter ; Kapp-Schwörer, Silke ; Späth, Daniela ; Kindler, Thomas ; Schittenhelm, Marcus ; Krauter, Jürgen ; Ganser, Arnold ; Göhring, Gudrun ; Schlegelberger, Brigitte ; Schlenk, Richard F. ; Döhner, Hartmut ; Döhner, Konstanze
Assuntos: Adult ; Aged ; Chromosomes, Human, Pair 13 ; Chromosomes, Human, Pair 9 ; Clonal Evolution - genetics ; DNA (Cytosine-5-)-Methyltransferases - genetics ; DNA Fingerprinting ; Female ; Gene Deletion ; Humans ; Leukemia, Myeloid, Acute - diagnosis ; Leukemia, Myeloid, Acute - epidemiology ; Leukemia, Myeloid, Acute - genetics ; Male ; Middle Aged ; Nuclear Proteins - genetics ; Polymorphism, Single Nucleotide - genetics ; Prognosis ; Recurrence ; Risk Factors ; Young Adult
É parte de: Blood, 2013-07, Vol.122 (1), p.100-108
Descrição: Mutations in the nucleophosmin 1 (NPM1) gene are considered a founder event in the pathogenesis of acute myeloid leukemia (AML). To address the role of clonal evolution in relapsed NPM1-mutated (NPM1mut) AML, we applied high-resolution, genome-wide, single-nucleotide polymorphism array profiling to detect copy number alterations (CNAs) and uniparental disomies (UPDs) and performed comprehensive gene mutation screening in 53 paired bone marrow/peripheral blood samples obtained at diagnosis and relapse. At diagnosis, 15 aberrations (CNAs, n = 10; UPDs, n = 5) were identified in 13 patients (25%), whereas at relapse, 56 genomic alterations (CNAs, n = 46; UPDs, n = 10) were detected in 29 patients (55%) indicating an increase in genomic complexity. Recurrent aberrations acquired at relapse included deletions affecting tumor suppressor genes (ETV6 [n = 3], TP53 [n = 2], NF1 [n = 2], WT1 [n = 3], FHIT [n = 2]) and homozygous FLT3 mutations acquired via UPD13q (n = 7). DNMT3A mutations (DNMT3Amut) showed the highest stability (97%). Persistence of DNMT3Amut in 5 patients who lost NPM1mut at relapse suggests that DNMT3Amut may precede NPM1mut in AML pathogenesis. Of note, all relapse samples shared at least 1 genetic aberration with the matched primary AML sample, implying common ancestral clones. In conclusion, our study reveals novel insights into clonal evolution in NPM1mut AML. • Relapsed AML with NPM1 mutation is genetically related to the primary leukemia and characterized by an increase in high-risk aberrations.• DNMT3A mutations show the highest stability and thus may precede NPM1 mutations.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia

United States: Elsevier Inc

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