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Pyjacker Identifies Enhancer Hijacking Events in Acute Myeloid Leukemia Including MNX1 Activation Via Deletion 7Q

crossref(2024)

Division of Cancer Epigenomics | Division of Neuroblastoma Genomics | Research Unit Apoptosis in Hematopoietic Stem Cells | Department of Internal Medicine III | Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) | Division Systems Biology of Signal Transduction | Division Applied Bioinformatics | National Center for Tumor Diseases (NCT) | Biomedical Informatics | Department of Medicine I | Department of Hematology and Oncology | Hematology | Interventional Immunology | MLL Munich Leukemia Laboratory | Department of Hematology | German Cancer Consortium (DKTK)

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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][1])(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. Statement of significance This study examines the consequences of structural alterations and demonstrates that proto-oncogene activation by enhancer hijacking is an overlooked pathomechanism in AML. MNX1 overexpression demonstrates that deletions on chromosome 7q can not only lead to haploinsufficiency, but also to activation of oncogenes by enhancer hijacking, providing a novel leukemogenic mechanism. ### Competing Interest Statement UHT is currently employed at Oxford Nanopore Technologies. EJ is currently employed at AstraZeneca. LB has received honoraria from AbbVie, Amgen, Astellas, BristolMyers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Roche, and Sanofi, as well as research support from Bayer and Jazz Pharmaceuticals. DBL received honoraria from Infectopharm GmbH. All other authors declared no conflict of interest. [1]: #ref-7
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要点】:本研究提出了一种计算工具pyjacker,用于检测急性髓细胞性白血病(AML)中的增强子劫持事件,发现了MNX1基因的异常激活,并揭示了其作为AML中一个被忽视的致白血病机制的创新点。

方法】:研究团队开发了pyjacker工具,该工具能够识别基因组重排导致的增强子异常定位,进而识别出原癌基因的异常表达。

实验】:通过对39例复杂核型AML样本的分析,pyjacker成功识别了MNX1基因的增强子劫持事件,这一事件通常与染色体7q的删除(del(7)(q22q36))相关。实验还通过MNX1基因敲除的异种移植模型,证明了MNX1是AML细胞生长的依赖基因,其敲除可降低白血病细胞的适应性。