Although most acute myeloid leukaemia (AML) patients initially respond to chemotherapy, the majority subsequently relapses and succumbs to refractory disease.
Residual leukaemic cells that survived chemotherapy may persist over time and later cause the disease to come back.
The researchers investigated if such minimal residual disease (MRD) was associated with specific acquired DNA mutations and if so, how would such mutations promote resistance to chemotherapy.
DNMT3A R882 mutations, but not other genetic alterations, were a strong predictor of MRD and were associated with adverse outcome in a large cohort of AML patients.
To investigate the role of mutant DNMT3A in AML pathogenesis and chemoresistance, they introduced this mutation into a mouse model.
DNMT3A alone did not cause leukaemia in mice; however DNMT3A-mutant haematopoietic stem cells could persist much longer than non-mutant cells, particularly under stress conditions, including after DNA damaging chemotherapy.
Moreover, mutant DNMT3A potently accelerated leukaemia in concert with Flt3ITD and Npm1c mutations.
On a molecular level DNMT3A-mutant cells failed to survey their DNA for the signs of damage, leading to reduced DNA repair, enhanced survival, and accumulation of additional mutations after chemotherapy.
Their data provide a novel mechanism by which mutant DNMT3A promotes chemoresistance in leukaemia cells, and suggest the possibility of unique vulnerabilities that can be exploited therapeutically in this common AML subtype.
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