DNMT3A Haploinsufficiency Transforms FLT3 ITD Myeloproliferative Disease into AML

Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis, but the molecular mechnism of the double-mutant is unknown. By using a rapid mouse model of FLT3/DNMT3A-Mutant AML and advanced global scRNAseq and methylation profiling techniques, the study demonstrates that DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3 ITD -mutant myeloproliferative neoplasm into AML.