Enhancer hijacking discovery in acute myeloid leukemia by pyjacker identifies MNX1 activation via deletion 7q.

Abstract

Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. Genomic rearrangements that reposition active enhancers near proto-oncogenes, leading to their aberrant expression, have not been systematically investigated in AML. 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 occurs in 1.4% of AML patients and shows 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.