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

Weichenhan, D.; Riedel, A.; Sollier, E.; Toprak, U. H.; Hey, J.; Breuer, K.; Wierzbinska, J. A.; Touzart, A.; Lutsik, P.; Baehr, M.; Oestlund, A.; Nilsson, C.; Jacobsson, S.; Edler, M.; Waraky, A.; Behrens, Y. L.; Goehring, G.; Schlegelberger, B.; Steinek, C.; Harz, H.; Leonhardt, H.; Dolnik, A.; Reinhardt, D.; Bullinger, L.; Palmqvist, L.; Lipka, D. B.; Plass, C.

doi:10.1101/2023.09.13.557546

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bioRxiv · 10.1101/2023.09.13.557546

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

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Abstract

Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor clinical outcome. The expected oncofusion between breakpoint partners (MNX1 and ETV6) has only been reported in a subset of cases. However, a universal feature is the strong transcript and protein expression of MNX1, a homeobox transcription factor that is normally not expressed in hematopoietic cells. Here, we map the translocation breakpoints on chromosomes 7 and 12 in affected patients to a region proximal to MNX1 and 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 an enhancer-hijacking event that explains MNX1 overexpression in hematopoietic cells. Our data suggest that enhancer-hijacking is a more common and overlooked mechanism for structural rearrangement-mediated gene activation in AML. Key pointsO_LIExpression analysis of over 1500 pediatric AML samples demonstrates MNX1 expression as a universal feature of t(7;12)(q36;p13) AML as well as in rare cases without t(7;12)(q36;p13) C_LIO_LIMNX1 is activated by an enhancer-hijacking event in t(7;12)(q36;p13) AML and not, as previously postulated, by the creation of a MNX1::ETV6 oncofusion gene. C_LI

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Weichenhan, D., Riedel, A., Sollier, E., Toprak, U. H., Hey, J., Breuer, K., Wierzbinska, J. A., Touzart, A., Lutsik, P., Baehr, M., Oestlund, A., Nilsson, C., Jacobsson, S., Edler, M., Waraky, A., Behrens, Y. L., Goehring, G., Schlegelberger, B., Steinek, C., Harz, H., Leonhardt, H., Dolnik, A., Reinhardt, D., Bullinger, L., Palmqvist, L., Lipka, D. B., Plass, C.. 2023-09-17. Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13). https://doi.org/10.1101/2023.09.13.557546

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