Enhancer Hijacking in Hematological Malignancies

Cell identity is established by tightly regulated transcriptional programs. Disruption of the regulatory mechanisms governing these programs leads to aberrant behavior and, frequently, cancer. Enhancer hijacking, the process whereby a gene comes under the control of an ectopic enhancer, is a major cause of transcriptional dysregulation. Although recognized since the 1980s, its detection has been traditionally hindered by the low resolution of karyotyping and incomplete knowledge of enhancer biology. This has changed with the development of high-throughput sequencing, leading to a surge in newly identified enhancer hijacking events over the past two decades. Furthermore, functional dissection of enhancers using techniques such as CRISPR/Cas9 has shed light on their mechanistic underpinnings, with acute myeloid leukemia (AML) emerging as a paradigm for this phenomenon. In this review, we outline the historical development of enhancer hijacking, highlight representative examples in hematological malignancies, and discuss the insights derived from this research, particularly in AML.