Enhancer-hijacking in Acute Myeloid Leukemia (AML)

Le September 19 2023 at 11h30 Séminaire

Acute myeloid leukemia (AML) with translocation t(7;12)(q36;p13) is a subgroup that occurs only in infants or very young children and is characterized by poor outcome. Its deep molecular characterization has been hampered by the rarity of this AML subtype and the lack of model systems. Approximately 50% of AML with t(7;12)(q36;p13) express a MNX1::ETV6 oncofusion transcript, but there is no evidence for the presence of an oncofusion protein. However, a universal feature is the strong RNA and protein expression of MNX1, a homeobox transcription factor that is normally not transcribed in hematopoietic cells. Here, we use whole genome sequencing to precisely map the translocation breakpoints on chromosomes 7 and 12 in affected patients to a region downstream of MNX1 on chromosome 7 and either introns 1 or 2 of ETV6 on chromosome 12. We confirm the tight association of MNX1 overexpression in t(7;12)(q36;p13) AML in our own samples and two additional cohorts of pediatric AML. The overall frequency of MNX1 overexpression in these two cohorts, totalling to 1556 pediatric AML, is 1.9% and includes all t(7;12) AML cases. Using an iPSC cell line, which has been CRISPR-engineered to harbor the t(7;12)(q36;p13) translocation (ChiPSC22^t(7;12)), we unravel an enhancer-hijacking event leading to MNX1 overexpression. Identification of enhancer regions in hematopoietic stem and progenitor cells derived from differentiated ChiPSC22^t(7;12) cells allowed us to demonstrate their importance for MNX1 expression in CRISPR knock-out experiments and by measuring the promoter-enhancer distance in confocal microscopy. In contrast to the prevailing dogma in AML, suggesting that translocations lead to the creation of oncofusion genes, t(7;12)(q36;p13) AML is characterized by the haploinsufficiency of ETV6 and an enhancer-hijacking event driving the expression of a novel leukemia oncogene, MNX1.