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

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.

Dissecting infant leukemia developmental origins with a hemogenic gastruloid model

“…We explored the utility of the hemogenic gastruloid model in understanding the cellular consequences of oncogenic events putatively initiated during development. We elected to investigate MNX1 -driven AML, the most common of infant-unique forms of AML, which we and others (Ingenhag et al, 2019; Ragusa et al, 2022; Waraky et al, 2022) have shown to be incapable of transforming adult cells.…”

“…Its overexpression does not result in leukemic transformation of neonatal cord blood cells or adult mouse bone marrow, but blocks erythroid differentiation and results in cellular senescence (Ingenhag et al, 2019;Waraky et al, 2022;Wildenhain et al, 2010;Wildenhain et al, 2012).…”

“…The most common of these is the translocation t(7;12)(q36;p13), a deadly form of AML molecularly characterized by ectopic activation of the MNX1 gene at 7q36 (Espersen et al, 2018). Its overexpression does not result in leukemic transformation of neonatal cord blood cells or adult mouse bone marrow, but blocks erythroid differentiation and results in cellular senescence (Ingenhag et al, 2019; Waraky et al, 2022; Wildenhain et al, 2010; Wildenhain et al, 2012). Engineering of the t(7;12) translocation in human iPS cells captures some of the transcriptional characteristics of t(7;12) patients and enhances erythroid and myeloid differentiation, but has not been shown to result in transformation (Nilsson et al, 2022).…”

Mechanisms associated with t(7;12) acute myeloid leukaemia: from genetics to potential treatment targets

“…While the MLL/ENL fusion was able to transform HSCs in serial re-plating colony-forming cell (CFC) assays, MNX1/ETV6 with or without overexpression of MNX1 did not confer self-renewal capacity. A recent pre-print has also failed to detect leukaemogenic potential of MNX1/ETV6 fusion-transduced foetal liver (FL) cells in mouse transplantation experiments [ 55 ]. However, the authors described an i n vitro myeloid differentiation bias of cells transduced with the fusion transcript.…”

“…However, the authors described an i n vitro myeloid differentiation bias of cells transduced with the fusion transcript. Significantly, no effects of MNX1/ETV6 were detected in adult bone marrow (BM) cells [ 55 ], hinting at the proposed in utero origins of t(7;12) leukaemia. Overall, with a MNX1/ETV6 protein still not identified, the role of the fusion transcript has remained questionable.…”