The clinical mutatome of core binding factor leukemia.

Abstract

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.

• Authors: Sabrina Opatz, Stefanos A Bamopoulos, Klaus H Metzeler, Tobias Herold, Bianka Ksienzyk, Kathrin Bräundl, Sebastian Tschuri, Sebastian Vosberg, Nikola P Konstandin, Christine Wang, Luise Hartmann, Alexander Graf, Stefan Krebs, Helmut Blum, Stephanie Schneider, Christian Thiede, Jan Moritz Middeke, Friedrich Stölzel, Christoph Röllig, Johannes Schetelig, Gerhard Ehninger, Alwin Krämer, Jan Braess, Dennis Görlich, Maria Cristina Sauerland, Wolfgang E Berdel, Bernhard J Wörmann, Wolfgang Hiddemann, Karsten Spiekermann, Stefan K Bohlander, Philipp A Greif
• Journal: Leukemia (Leukemia) Vol. 34 Issue 6 Pg. 1553-1562 (06 2020) ISSN: 1476-5551 [Electronic] England
• PMID: 31896782 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Core Binding Factors

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Core Binding Factors (genetics)
• Female
• Humans
• Leukemia, Myeloid, Acute (genetics)
• Male
• Middle Aged
• Mutation
• Young Adult