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Abstract

Acute myeloid leukemia (AML) is a cancer of blood cells, in which hematopoietic progenitor cells have their differentiation impaired and proliferate excessively. This is a heterogeneous disease with many subtypes. While new treatments have been developed for several subtypes, which have led to great improvements in survival, one subtype which still retains a dismal prognosis is AML with a complex karyotype (ckAML). It is defined by the presence of at least three cytogenetic abnormalities and is still poorly understood at the molecular level. Genomic studies have identified that copy number alterations (CNAs) are very frequent in ckAML, especially deletions which occur predominantly in the chromosome arms 5q, 7q, 17p and 12p. However, for the most part, it is still unknown how these deletions might drive the disease.

Here, I hypothesized that the numerous genomic rearrangements in ckAML might, in addition to the CNAs, lead to the aberrant expression of oncogenes by repositioning them in the vicinity of active enhancers. Such "enhancer hijacking" events are known to occur in many cancer types, but in AML only a few genes have been reported to be activated by this mechanism. Thirty-nine ckAML samples were profiled with whole genome sequencing (WGS) and RNA-seq. I analyzed the somatic alterations and the transcriptomes of these samples, and confirmed the high frequency of \textit{TP53} mutations, deletions and chromothripsis events. I developed a tool called pyjacker to systematically search for enhancer hijacking events. This led to the identification of 19 genes activated by structural rearrangements, including known genes like \textit{MECOM}, \textit{BCL11B} and \textit{MNX1}, as well as novel genes like \textit{EPO} and \textit{GSX2}. I further analyzed nanopore sequencing data from a subset of these samples, and found that enhancer hijacking can result in allele-specific alterations in the DNA methylation profile, although these changes are modest.

Taken together, these results show that enhancer hijacking plays a more important role in ckAML than previously thought. Studying the genes activated by this mechanism could lead to novel targeted therapies. Nevertheless, enhancer hijacking is not as recurrent in ckAML as the most common deletions like del(5q) and del(7q), so studying how these deletions drive ckAML might be the most promising route towards improving therapies for ckAML patients.