Acute myeloid leukemia (AML) is a rapidly progressing, hard-to-treat blood cancer. In approximately one-fifth of patients, the DNMT3A gene is mutated at arginine 882 (R882), most commonly to histidine (R882H) or cysteine (R882C). AML with mutated DNMT3A is usually resistant to the chemotherapy drug daunorubicin, but the mechanism isn’t clear. To learn more, researchers recently compared wild- type and DNMT3A R882H AML cell lines. The mutant cells were more proliferative, more resistant to apoptosis, and less sensitive to daunorubicin than the wild-type cells. The mutant cells also exhibited altered NRF2 signaling. Specifically, the R882H mutation upregulated NRF2 expression by increasing NRF2 protein stability without affecting methylation, and daunorubicin treatment activated the NRF2/NQO1 pathway in the mutant cells. Inhibiting the NRF2 pathway with brusatol sensitized the mutant cells to daunorubicin, confirming the role of NRF2 in chemoresistance. Although in vivo studies are needed, these findings reveal that the DNMT3A R882H mutation mediates daunorubicin resistance in AML via NRF2 and identify NRF2 as a potential therapeutic target for AML in patients with this mutation.