Mutations in TP53( TP53mut) are present in roughly 10% of acute myeloid leukemia (AML) patients and represent a unique subgroup of patients with very poor prognosis. While the exact mechanisms of TP53mut-driven leukemogenesis remain elusive, transcriptional changes associated with suppression of the TP53 signaling pathway are considered to confer a dismal prognosis on TP53mut patients. Using molecular profiling of a large cohort of AML patients (n=823) we identify a new poor prognostic subgroup in AML that is TP53 WTbut shares strong similarities with TP53mut patients. Patients included in this new group present increased expression of the oncogenic TP73gene isoform ΔNp73,which lacks the transactivation domain but still binds to chromatin. We find that the transcriptional and metabolic program of ΔNp73highAMLs strongly resembles that of TP53mut AML, being enriched for stemness signatures like “17LSC” and “LSC UP”. In line with TP53mut AML, ΔNp73high/ TP53WTfrequently co-occurs with U2AF1, SRSF2, TET2, and RUNX1mutations .Lentiviral overexpression (OE) of ΔNp73 in healthy CD34 +cells increased cell proliferation and stemness. ΔNp73-OE in TP53WTAML models, imposed drug resistance against several standard-of-care cytotoxic therapies in AML (e.g., AraC, venetoclax (VEN) ± azacytidine (AZA), and FLT3 inhibitors), while drug resistance was not further enhanced upon ΔNp73-OE in TP53mut AML models. These results were validated using ex vivotreated primary AML samples (n=80), whereby ΔNp73 highsamples were more resistant to several cytotoxic therapies, including VEN+AZA .Lentiviral ΔNp73-OE in primary APL samples (n=10) allowed efficient engraftment in vivousing xenograft mouse models with colonization of secondary organs and splenomegaly, which was not observed in the empty vector controls.