Mnx1 Induces Leukemia Transformation Through Altering Histone Methylation in a Model of Pediatric t(7;12) Acute Myeloid Leukemia.

Waraky, A.; Ostlund, A.; Nilsson, T.; Weichenhan, D.; Lutsik, P.; Baehr, M.; Hey, J.; Adamsson, J.; Morsy, M. H. A.; Li, S.; Fogelstrand, L.; Plass, C.; Palmqvist, L.

doi:10.1101/2022.06.10.495634

bioRxiv · 10.1101/2022.06.10.495634

Mnx1 Induces Leukemia Transformation Through Altering Histone Methylation in a Model of Pediatric t(7;12) Acute Myeloid Leukemia.

Waraky, A.·Ostlund, A.·Nilsson, T.·Weichenhan, D.·Lutsik, P.·Baehr, M.·Hey, J.·Adamsson, J.·Morsy, M. H. A.·Li, S.·Fogelstrand, L.·Plass, C.·Palmqvist, L.

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Abstract

Certain subtypes of acute myeloid leukemia (AML) in children have inferior outcome. One of these has a translocation t(7;12)(q36;p13) leading to a MNX1::ETV6 fusion along with high expression of MNX1. Here we identified the transforming event in this AML and possible ways of treatment. Only MNX1 was able to induce AML in mice, with similar gene expression and pathway enrichment to t(7;12) AML patient data. Importantly, this leukemia was only induced in immune incompetent mice using fetal but not adult hematopoietic stem and progenitor cells. The restriction in transforming capacity to cells from fetal liver is in alignment with t(7;12)(q36;p13) AML being mostly seen in infants. Expression of MNX1 led to increased histone 3 lysine 4 mono-, di- and trimethylation, reduction in H3K27me3, accompanied with changes in genome-wide chromatin accessibility and genome expression, likely mediated through MNX1 interaction with the methionine cycle and methyltransferases. MNX1 expression increased DNA damage, depletion of the Lin-/Sca1+/c-Kit+ population and skewing toward the myeloid lineage. These effects, together with leukemia development, was prevented by pretreatment with the S-adenosylmethionine analog Sinefungin. In conclusion, we have shown the importance of MNX1 in development of AML with t(7;12), supporting a rationale for targeting MNX1 and downstream pathways.

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Waraky, A., Ostlund, A., Nilsson, T., Weichenhan, D., Lutsik, P., Baehr, M., Hey, J., Adamsson, J., Morsy, M. H. A., Li, S., Fogelstrand, L., Plass, C., Palmqvist, L.. 2022-06-12. Mnx1 Induces Leukemia Transformation Through Altering Histone Methylation in a Model of Pediatric t(7;12) Acute Myeloid Leukemia.. https://doi.org/10.1101/2022.06.10.495634

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