Mnx1 Induces Leukemia Transformation Through Altering Histone Methylation in a Model of Pediatric Acute Myeloid Leukemia with t(7;12)(q36;p13)

Abstract

Abstract Certain subtypes of acute myeloid leukemia (AML) in children have still inferior outcome. One of these AML subtypes has a translocation t(7;12)(q36;p13), always leading to high expression of MNX1 and often to MNX1::ETV6 fusion expression. Here we identified the transforming event in this AML and possible ways to target them. Only MNX1 was able to induce AML in mice, and this was observed using hematopoietic stem and progenitor cells derived from fetal origin but not from adult bone marrow. The restriction in the transforming capacity to cells from fetal liver origin is in concordance with the fact that t(7;12)(q36;p13) AML is mostly restricted to infants. Ectopic expression of MNX1 led to increase of H3K4me1, H3K4me2 and H3K4me3, reduction in H3K27me3, accompanied with changes in genome-wide chromatin accessibility and genome expression, likely mediated through MNX1 interaction with the methionine cycle and different methyltransferases. MNX1 expression resulted in 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 the S-adenosylmethionine analog Sinefungin. In conclusion, we have shown the importance of MNX1 in leukemia development in AML with t(7;12), supporting a rationale for targeting MNX1 and downstream pathways.