Genomic heterogeneity in core-binding factor acute myeloid leukemia and its clinical implication

Nikolaus Jahn, Tobias Terzer, Eric Sträng, Anna Dolnik, Sibylle Cocciardi, Ekaterina Panina, Andrea Corbacioglu, Julia Herzig, Daniela Weber, Anika Schrade, Katharina Götze, Thomas Schröder, Michael Lübbert, Dominique Wellnitz, Elisabeth Koller, Richard F. Schlenk, Verena I. Gaidzik, Peter Paschka, Frank G. Rücker, Michael HeuserFelicitas Thol, Arnold Ganser, Axel Benner, Hartmut Döhner, Lars Bullinger, Konstanze Döhner

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16)(p13.1q22) and AML with t(8;21)(q22;q22.1). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. We comprehensively characterized the mutational landscape of 350 adult CBF-AML [inv(16): n = 160, t(8;21): n = 190] performing targeted sequencing of 230 myeloid cancer-associated genes. Apart from common mutations in signaling genes, mainly NRAS, KIT, and FLT3, both CBF-AML entities demonstrated a remarkably diverse pattern with respect to the underlying cooperating molecular events, in particular in genes encoding for epigenetic modifiers and the cohesin complex. In addition, recurrent mutations in novel collaborating candidate genes such as SRCAP (5% overall) and DNM2 (6% of t(8;21) AML) were identified. Moreover, aberrations altering transcription and differentiation occurred at earlier leukemic stages and preceded mutations impairing proliferation. Lasso-penalized models revealed an inferior prognosis for t(8;21) AML, trisomy 8, as well as FLT3 and KIT exon 17 mutations, whereas NRAS and WT1 mutations conferred superior prognosis. Interestingly, clonal heterogeneity was associated with a favorable prognosis. When entering mutations by functional groups in the model, mutations in genes of the methylation group (ie, DNMT3A, TET2) had a strong negative prognostic impact.

Original languageEnglish
Pages (from-to)6342-6352
Number of pages11
JournalBlood Advances
Volume4
Issue number24
DOIs
StatePublished - 22 Dec 2020
Externally publishedYes

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