Background: Deletions in the long arm of chromosome 7 (del7q) are recurrent events in acute myeloid leukemia (AML) which are associated with an unfavorable outcome. Since the search for recessive tumor suppressor genes located within the deleted region was unsuccessful, the prevalent idea currently is that haploinsufficiency of one or more tumor suppressor genes drive this leukemia. Other studies showed that structural rearrangements such as translocations and inversions can lead to the activation of oncogenes through relocation of cis-regulatory elements. A similar mechanism would also be plausible for chromosomal deletions, specifically del(7q) in AML.
Aims:We investigated the hypothesis that del(7q) could activate a proto-oncogene located outside the deleted region due to restructuring of topologically associating domains and relocation of cis-regulatory elements.Methods: Whole genome sequencing (WGS), RNA sequencing (RNAseq) and Infinium MethylationEPIC array were used to study 13 patients with isolated del(7q) or monosomy 7. Epigenomic profiling using antibody-guided chromatin tagmentation with sequencing (ACT-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq) and circular chromosome conformation capture (4C) was done on primary AML samples with MNX1 activation. CRISPR/Cas9 genome editing was used to generate model systems for the putative enhancer hijacking event.Results: We identified a subgroup of del(7q)-AML that aberrantly expresses Motor Neuron and Pancreas Homeobox (MNX1), which is a key developmental homeobox gene located on chromosome 7q36.3 coding for the transcription factor MNX1. MNX1 expression is usually tightly regulated and restricted to the brain, gastrointestinal tract and pancreas.
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