Fig. 2

DNMT3A alterations lead to epigenetic reprogramming in leukemia. Leukemia is a heterogeneous disease caused by cumulative multi-step disruption. In the initial stage of leukemogenesis, accumulated DNA lesions, emergent stimuli, and metabolic stress are observed in hematopoietic stem cells (HSCs). These conditions lead to gene alterations and link epigenetic reprogramming to leukemia development. Currently, DNMT3A gene lesions are considered to be critical epigenetic alterations in the occurrence of leukemia. In patient specimens and mouse models, the mutation or deletion of DNMT3A causes the apparent reversal of normal HSCs into pre-leukemia stem cells (Pre-LSCs). Frequently, Pre-LSCs are quiescent and stable in the early phases of leukemia. The accumulation of other transformative changes, such as a series of mutations (RAS^mut, NPM1^mut, c-Kit^mut) or oncogenic alterations (FLT3^ITD) causes Pre-LSCs to undergo malignant transformation into leukemia stem cells (LSCs), which finally enter the clonal expansion stage. Furthermore, during the aggressive progression of leukemia in a xenograft mouse model of OCI-AML3 with mutated DNMT3A, DNMT3A mutation promotes leukemic extramedullary infiltration by up-regulating the expression of the EMT inducer TWIST1. HSCs: hematopoietic stem cells; Pre-LSCs: pre-leukemia stem cells; LSCs: leukemia stem cells; mut: mutation; del: deletion; ITD: internal tandem duplication; OE: overexpression; EMT: epithelial-mesenchymal transition