Open Access

Etienne Sollier, Anna Riedel, Umut H. Toprak, Justyna A. Wierzbinska, Dieter Weichenhan, Jan Philipp Schmid, Mariam Hakobyan, Aurore Touzart, Ekaterina Jahn, Binje Vick, Fiona Brown-Burke, Katherine Kelly, Simge Kelekci, Anastasija Pejkovska, Ashish Goyal, Marion Bähr, Kersten Breuer, Mei-Ju May Chen, Maria Llamazares-Prada, Mark Hartmann, Maximilian Schönung, Nadia Correia, Andreas Trumpp, Yomn Abdullah, Ursula Klingmüller, Sadaf S. Mughal, Benedikt Brors, Frank Westermann, Elias Ulrich, Robert J. Autry, Matthias Schlesner, Sebastian Vosberg, Tobias Herold, Philipp A. Greif, Dietmar Pfeifer, Michael Lübbert, Thomas Fischer, Florian H. Heidel, Claudia Gebhard, Wencke Walter, Torsten Haferlach, Ann-Kathrin Eisfeld, Krzysztof Mrózek, Deedra Nicolet, Lars Bullinger, Leonie Smeenk, Claudia Erpelinck-Verschueren, Roger Mulet-Lazaro, Ruud Delwel, Aurélie Ernst, Michael Scherer, Pavlo Lutsik, Irmela Jeremias, Konstanze Döhner, Hartmut Döhner, Daniel B. Lipka, Christoph Plass

• Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. Genomic rearrangements can reposition active enhancers near proto-oncogenes, leading to their aberrant expression, however, a comprehensive understanding of these events in AML is still incomplete. To facilitate the discovery of such “enhancer hijacking” events, we developed pyjacker, a computational tool, and applied it to 39 ckAML samples. Pyjacker identified several enhancer hijacking events in AML patient samples, including aberrant expression of motor neuron and pancreas homeobox 1 (MNX1), which can result from del(7)(q22q36) and is associated with hijacking of a CDK6 enhancer. MNX1 activation occurred in 1.4% of AML patients and showed significant co-occurrence with BCOR mutations. Through a xenograft mouse model, we demonstrated that MNX1 is required for leukemia cell fitness. Pyjacker is an easy-to-use, accurate, and broadlyAcute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. Genomic rearrangements can reposition active enhancers near proto-oncogenes, leading to their aberrant expression, however, a comprehensive understanding of these events in AML is still incomplete. To facilitate the discovery of such “enhancer hijacking” events, we developed pyjacker, a computational tool, and applied it to 39 ckAML samples. Pyjacker identified several enhancer hijacking events in AML patient samples, including aberrant expression of motor neuron and pancreas homeobox 1 (MNX1), which can result from del(7)(q22q36) and is associated with hijacking of a CDK6 enhancer. MNX1 activation occurred in 1.4% of AML patients and showed significant co-occurrence with BCOR mutations. Through a xenograft mouse model, we demonstrated that MNX1 is required for leukemia cell fitness. Pyjacker is an easy-to-use, accurate, and broadly applicable tool for identifying consequences of genomic events driving tumorigenesis, especially when germline genomic data is missing.…