Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in veryyoung children and has a poor outcome. The expected oncofusion between breakpointpartners (MNX1 and ETV6) has only been reported in a subset of cases. However, a universalfeature is the strong transcript and protein expression of MNX1, a homeobox transcriptionfactor that is normally not expressed in hematopoietic cells. Here, we map the translocationbreakpoints on chromosomes 7 and 12 in affected patients to a region downstream of MNX1and either introns 1 or 2 of ETV6. The frequency of MNX1 overexpression in pediatric AML(n=1556, own and published data) is 2.4% and occurs predominantly in t(7;12)(q36;p13)AML. Chromatin interaction assays in a t(7;12)(q36;p13) iPSC cell line model unravel anenhancer-hijacking event that explains MNX1 overexpression in hematopoietic cells. Ourdata suggest that enhancer-hijacking is a more common and overlooked mechanism forstructural rearrangement-mediated gene activation in AML.