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

Certain subtypes of acute myeloid leukemia (AML) in children have still inferior outcome. One 25 of these AML subtypes has a translocation t(7;12)(q36;p13), always leading to high expression 26 of MNX1 and often to MNX1 :: ETV6 fusion expression. Here we identified the transforming 27 event in this AML and possible ways to target them. Only MNX1 was able to induce AML in 28 mice, and this was observed using hematopoietic stem and progenitor cells derived from fetal 29 origin but not from adult bone marrow. The restriction in the transforming capacity to cells 30 from fetal liver origin is in concordance with the fact that t(7;12)(q36;p13) AML is mostly 31 restricted to infants. Ectopic expression of MNX1 led to increase of H3K4me1, H3K4me2 and 32 H3K4me3, reduction in H3K27me3, accompanied with changes in genome-wide chromatin 33 accessibility and genome expression, likely mediated through MNX1 interaction with the 34 methionine cycle and different methyltransferases. MNX1 expression resulted in increased 35 DNA damage, depletion of the Lin-/Sca1+/c-Kit+ population and skewing toward the myeloid 36 lineage. These effects, together with leukemia development, was prevented by the S- 37 adenosylmethionine analog Sinefungin. In conclusion, we have shown the importance of 38 MNX1 in leukemia development in AML with t(7;12), supporting a rationale for targeting 39 MNX1 and downstream pathways.

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