Journal Article

The clinical mutatome of core binding factor leukemia

Berdel, Wolfgang E, Sauerland, Maria Cristina, Schetelig Johannes, Metzeler, Klaus H, Bohlander, Stefan K, Krebs, Stefan, Wang, Christine, Schneider, Stephanie, Middeke Jan Moritz, Konstandin, Nikola P, Röllig Christoph, Vosberg Sebastian, Wörmann, Bernhard J, Opatz Sabrina, Braess, Jan, Bräundl Kathrin, Ksienzyk Bianka, Krämer Alwin, Stölzel Friedrich, Hartmann Luise, Blum, Helmut, Tschuri Sebastian, Görlich, Dennis, Spiekermann Karsten, Graf, Alexander, Herold, Tobias, Thiede, Christian, Ehninger Gerhard, Greif, Philipp A, Bamopoulos, Stefanos A, Hiddemann Wolfgang

2020

Overview

The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10–15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum (‘mutatome’) in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11- and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2, and ZBTB7A being strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A, and DHX15 and identified novel, recurrent mutations in NFE2 (3%), MN1 (4%), HERC1 (3%), and ZFHX4 (5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia.

• Publisher: Nature Publishing Group
• Subject: Acute myeloid leukemia / Binding / Chemotherapy / Chromosomes / Gene sequencing / Genes / Janus kinase 2 / Leukemia / Leukemogenesis / Medical prognosis / Mutation / Myeloid leukemia / Patients / Runx1 protein / Subgroups / Y chromosomes