Proteomics

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


ABSTRACT: Acute myeloid leukemia (AML) in children with cytogenetic aberrations like translocation t(7;12)(q36;p13) is associated with inferior outcome. The translocation can lead to a fusion transcript MNX1::ETV6 but also to activation of MNX1 transcription. We generated an AML mouse model by transplantation of fetal liver cells with ectopic expression of MNX1. AML was highly penetrant in immunocompromised and less penetrant in immunocompetent mice. Transforming capacity was restricted to fetal liver cells and could not achieved with adult bone marrow cells, in concordance with the clinical finding that t(7;12)(q36;p13) is mostly restricted to infants. Ectopic expression of MNX1 led to increased H3K4methylation and reduced H3K27me3, possibly through its interaction with methyl transferases. MNX1 expression was accompanied with changes in genome wide chromatin accessibility , increased DNA damage, depletion in the LSK population and skewing toward the myeloid lineage. These effects, together with leukemia development, could be prevented by the S-adenosylmethionine analogue Sinefungin that acts as a SAM competitor and a pan methyltranferases inhibitor. Expression profiles of a human iPSC AML model with t(7;12) and of TARGET pediatric AML and TCGA patients support the rationale for targeting MNX1 and downstream pathways.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Johannes Fuchs  

LAB HEAD: Lars Palmqvist

PROVIDER: PXD034416 | Pride | 2024-09-30

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
QEHF_190827_05.msf Msf
QEHF_190827_05.raw Raw
QEHF_190827_08.msf Msf
QEHF_190827_08.raw Raw
QEHF_190827_11.msf Msf
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Publications

Aberrant MNX1 expression associated with t(7;12)(q36;p13) pediatric acute myeloid leukemia induces the disease through altering histone methylation.

Waraky Ahmed A   Östlund Anders A   Nilsson Tina T   Weichenhan Dieter D   Lutsik Pavlo P   Bähr Marion M   Hey Joschka J   Tunali Gürcan G   Adamsson Jenni J   Jacobsson Susanna S   Morsy Mohammad Hamdy Abdelrazak MHA   Li Susann S   Fogelstrand Linda L   Plass Christoph C   Palmqvist Lars L  

Haematologica 20240301 3


Certain subtypes of acute myeloid leukemia (AML) in children have inferior outcome, such as AML with translocation t(7;12)(q36;p13) leading to an MNX1::ETV6 fusion along with high expression of MNX1. We have identified the transforming event in this AML and possible ways of treatment. Retroviral expression of 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  ...[more]

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