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 Baehr, Kersten Breuer, Mei-Ju May Chen, Maria Llamazares-Prada, Mark Hartmann, Maximilian Schoenung, Nadia Correia, Andreas Trumpp, Yomn Abdullah, Ursula Klingmueller, Sadaf S. Mughal, Benedikt Brors, Frank Westermann, Matthias Schlesner, Sebastian Vosberg, Tobias Herold, Philipp A. Greif, Dietmar Pfeifer, Michael Luebbert, Thomas Fischer, Florian Heidel, Claudia Gebhard, Wencke Walter, Torsten Haferlach, Ann-Kathrin Eisfeld, Krzysztof Mrozek, Deedra Nicolet, Lars Bullinger, Leonie Smeenk, Claudia Erpelinck, Roger Mulet-Lazaro, Ruud Delwel, Aurelie Ernst, Michael Scherer, Pavlo Lutsik, Irmela Jeremias, Konstanze Doehner, Hartmut Doehner, Daniel B. Lipka, Christoph Plass
{"title":"Pyjacker 发现急性髓性白血病中的增强子劫持事件，包括通过 7q 缺失激活 MNX1","authors":"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 Baehr, Kersten Breuer, Mei-Ju May Chen, Maria Llamazares-Prada, Mark Hartmann, Maximilian Schoenung, Nadia Correia, Andreas Trumpp, Yomn Abdullah, Ursula Klingmueller, Sadaf S. Mughal, Benedikt Brors, Frank Westermann, Matthias Schlesner, Sebastian Vosberg, Tobias Herold, Philipp A. Greif, Dietmar Pfeifer, Michael Luebbert, Thomas Fischer, Florian Heidel, Claudia Gebhard, Wencke Walter, Torsten Haferlach, Ann-Kathrin Eisfeld, Krzysztof Mrozek, Deedra Nicolet, Lars Bullinger, Leonie Smeenk, Claudia Erpelinck, Roger Mulet-Lazaro, Ruud Delwel, Aurelie Ernst, Michael Scherer, Pavlo Lutsik, Irmela Jeremias, Konstanze Doehner, Hartmut Doehner, Daniel B. Lipka, Christoph Plass","doi":"10.1101/2024.09.11.611224","DOIUrl":null,"url":null,"abstract":"Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"6 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q\",\"authors\":\"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 Baehr, Kersten Breuer, Mei-Ju May Chen, Maria Llamazares-Prada, Mark Hartmann, Maximilian Schoenung, Nadia Correia, Andreas Trumpp, Yomn Abdullah, Ursula Klingmueller, Sadaf S. Mughal, Benedikt Brors, Frank Westermann, Matthias Schlesner, Sebastian Vosberg, Tobias Herold, Philipp A. Greif, Dietmar Pfeifer, Michael Luebbert, Thomas Fischer, Florian Heidel, Claudia Gebhard, Wencke Walter, Torsten Haferlach, Ann-Kathrin Eisfeld, Krzysztof Mrozek, Deedra Nicolet, Lars Bullinger, Leonie Smeenk, Claudia Erpelinck, Roger Mulet-Lazaro, Ruud Delwel, Aurelie Ernst, Michael Scherer, Pavlo Lutsik, Irmela Jeremias, Konstanze Doehner, Hartmut Doehner, Daniel B. Lipka, Christoph Plass\",\"doi\":\"10.1101/2024.09.11.611224\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML.\",\"PeriodicalId\":501233,\"journal\":{\"name\":\"bioRxiv - Cancer Biology\",\"volume\":\"6 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-09-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"bioRxiv - Cancer Biology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2024.09.11.611224\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv - Cancer Biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.09.11.611224","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q
Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML.
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