An oncogenic enhancer-rearrangement causes concomitant deregulation of EVI1 and GATA2 in leukemia. Targeted resequencing of chromosomal regions centered on 3q21 and 3q26 in conjunction with RNA-Seq from Acute Myeloid Leukemia patients.

Chromosomal rearrangements without gene-fusions have been implicated in leukemogenesis by causing deregulation of proto-oncogenes via relocation of cryptic regulatory DNA elements. AML with inv(3)/t(3;3) is associated with aberrant expression of the stem-cell regulator EVI1. Applying functional genomics and genome-engineering, we demonstrate that both 3q-rearrangements reposition a distal GATA2 enhancer to ectopically activate EVI1 and simultaneously confer GATA2 functional haploinsufficiency, previously identified as the cause of sporadic familial AML/MDS and MonoMac/Emberger syndromes. Genomic excision of the ectopic enhancer restored EVI1 silencing and led to growth inhibition and differentiation of AML cells, which could be replicated by pharmacologic BET-inhibition. Our data show that structural rearrangements involving chromosomal repositioning of enhancers can cause deregulation of two unrelated distal genes, with cancer as the outcome.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

2 Datasets

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Dataset ID	Description	Technology	Samples
EGAD00001000726	In total 30 Acute Myeloid Leukemias with an acquired inv(3)(q21q26) or t(3;3)(q21;q26) have been characterized by whole transcriptome sequencing (RNA-Seq). The 3q-aberration leads to overexpression of the proto-oncogene EVI1, but the mechanism of overexpression has thus far been elusive. The RNA-Seq was integral in determining the precise enhancer inducing the overexpression and led to other key discoveries.	Illumina HiSeq 2500	30
EGAD00001000727	Targeted resequencing on the specific regions chr3:126036241-130672290 and chr3:157712147-175694147 in hg19 centered on the chromosomal regions 3q21 and 3q26 respectively. The focus lies on the detection of the exact breakpoints in Acute Myeloid Leukemia (AML) patients having acquired a inv(3)(q21q26) or t(3;3)(q21;q26). This dataset contains all information to detect all structural variants contained within these regions, including the 3q-aberrations inducing the overexpression of the proto-oncogene EVI1.	Illumina HiSeq 2500	38