Enhancer Hijacking Discovery in Acute Myeloid Leukemia by Pyjacker Identifies MNX1 Activation via Deletion 7q

作者：Etienne Sollier, Anna Riedel, Umut H. Toprak, Justyna A. Wierzbinska, Dieter Weichenhan, Jan Philipp Schmid, Mariam Hakobyan, Aurore Touzart, Nikolaus Jahn, Binje Vick, Fiona Brown-Burke, Katherine A. Kelly, Simge Kelekçi, Anastasija Pejkovska, Ashish Goyal, Marion Bähr, Kersten Breuer, Mei-Ju May Chen, Maria Llamazares Prada, Mark Hartmann, Maximilian Schönung, Nádia 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 · 发表于：Blood Cancer Discovery · 年份：2025 · DOI：10.1158/2643-3230.bcd-24-0278 · 被引用次数：6 · 研究领域：Acute Myeloid Leukemia Research、Cancer-related Molecular Pathways、Genomics and Chromatin Dynamics

Acute myeloid leukemia (AML) with complex karyotype 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 AML samples with complex karyotype. Pyjacker identified several enhancer hijacking events in AML patient samples, including aberrant expression of MNX1, which can result from del(7)(q22q36) and is associated with hijacking of a CDK6 enhancer. MNX1 activation occurred in 1.4% of patients with AML 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 are missing. SIGNIFICANCE: This study examines the consequences of structural alterations in AML and demonstrates that proto-oncogene activation by enhancer hijacking is an understudied pathomechanism. MNX1 overexpression demonstrates that deletions on chromosome 7q can not only lead to haploinsufficiency but also to activation of oncogenes by enhancer hijacking.