LAUSR

The transcription factor p53, described as the “guardian of the genome”, becomes activated in response to malignancyassociated stress signals resulting in cell cycle arrest, senescence, differentiation, or apoptosis leading to the inhibition of tumor cell growth [1]. Inactivation of the p53 tumorsuppressor pathway is among the most common escape mechanisms allowing survival of malignant cells subjected to cytotoxic stress [2]. Inactivating TP53 mutations have been detected in ≤50% of cancers [3]. Acute myeloid leukemia (AML) is an aggressive bone marrow (BM) malignancy associated with poor long-term survival in most patients. Somatic TP53 mutations occur in AML less frequently than in solid tumors, in 5–10% of de novo and ~33% of therapy-related or secondary AML cases [4–7]. They are associated with older age and poorrisk cytogenetic abnormalities [e.g., −5/del(5q), −7/del (7q) and complex karyotype, especially a “typical” complex karyotype] [8]. Patients with TP53 mutations have very poor outcomes, with complete remission (CR) rates of 20–40% and median overall survival (OS) of 5–9 months [5, 8, 9]. Even for patients attaining a CR, allogeneic stem cell transplantation (alloSCT) yields inadequate results with 3-year OS rates of 10–12% [10]. The TP53 gene, located at human chromosome location 17p13.1, consists of an acidic N-terminus transcription activation domain, a second activation domain, a proline rich domain, a central DNA-binding core domain, a nuclear localization signaling domain, an oligomerization domain, and a C-terminal. A second member of the p53 family is p73, a structural homolog of p53 expressed as multiple protein isoforms that vary in function [11]. The TP73 gene, located at 1p36.32, includes three structural elements similar to TP53, including DNA-binding, oligomerization, and transactivation domains. The p73 protein induces apoptosis similarly to p53 through activation of its downstream target genes. However, p73 also has functions distinct from p53 with roles in neuronal stem cell maintenance, aging and metabolism, and microRNA regulation [12]. TP73 is both overexpressed and deleted in cancers but very rarely mutated (<1%) [13]. Despite large sequencing efforts in AML, TP73 mutations have yet to be described, and it is unknown if they have similar prognostic implications to TP53 mutations. Therefore, we analyzed 1029 adults (aged ≥ 17 years) with newly diagnosed AML (excluding acute promyelocytic leukemia) using targeted next-generation sequencing (NGS) [7]. The patients were treated on Cancer and Leukemia Group B (CALGB) trials described in the Supplementary Information. Patients dying within 30 days of starting therapy and those who underwent alloSCT in first CR were excluded. Cytogenetic analyses of pretreatment BM and/or blood samples were performed by institutional, CALGB/Alliance for Clinical Trials in Oncology (Alliance)-approved laboratories, and the results confirmed by central karyotype review [14]. Treatment These authors contributed equally: John C. Byrd, Clara D. Bloomfield