ΔNp73 isoform defines a TP53-mutant-like poor-risk subgroup of acute myeloid leukemia

Diego A Pereira-Martins; Cesar Ortiz; Isabel Weinhäuser; Albertus T J Wierenga; Vincent van den Boom; Fatemeh Mojallali; Dominique Sternadt; Nisha K van der Meer; Shanna M Hogeling; Thiago M Bianco; Prodromos Chatzikyriakou; Douglas R Silveira; Emanuele Ammatuna; Antonio R Lucena-Araujo; Lynn Quek; Gerwin Huls; Eduardo M Rego; Jan Jacob Schuringa

doi:10.1016/j.xcrm.2025.102540

ΔNp73 isoform defines a TP53-mutant-like poor-risk subgroup of acute myeloid leukemia

Cell Rep Med. 2026 Jan 20;7(1):102540. doi: 10.1016/j.xcrm.2025.102540. Epub 2026 Jan 8.

Authors

Diego A Pereira-Martins¹, Cesar Ortiz², Isabel Weinhäuser³, Albertus T J Wierenga⁴, Vincent van den Boom⁴, Fatemeh Mojallali⁴, Dominique Sternadt⁴, Nisha K van der Meer⁴, Shanna M Hogeling⁴, Thiago M Bianco⁵, Prodromos Chatzikyriakou⁶, Douglas R Silveira⁶, Emanuele Ammatuna⁴, Antonio R Lucena-Araujo⁷, Lynn Quek⁶, Gerwin Huls⁴, Eduardo M Rego², Jan Jacob Schuringa⁸

Affiliations

¹ Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Medical Imaging, Haematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; Center for Cell Based Therapy, São Paulo Research Foundation, Ribeirão Preto, SP, Brazil; Hematology Division, LIM31, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil.
² Department of Medical Imaging, Haematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; Center for Cell Based Therapy, São Paulo Research Foundation, Ribeirão Preto, SP, Brazil; Hematology Division, LIM31, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil.
³ Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Medical Imaging, Haematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; Center for Cell Based Therapy, São Paulo Research Foundation, Ribeirão Preto, SP, Brazil.
⁴ Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁵ Department of Medical Imaging, Haematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; Center for Cell Based Therapy, São Paulo Research Foundation, Ribeirão Preto, SP, Brazil.
⁶ Myeloid Leukaemia Genomics and Biology Group, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.
⁷ Department of Genetics, Federal University of Pernambuco, Recife, Brazil.
⁸ Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address: j.j.schuringa@umcg.nl.

Abstract

Among acute myeloid leukemia (AML) patients, a subgroup remains notoriously refractory to current treatment options, with underlying mechanisms poorly understood. Here, using a multi-omics approach, we reveal that this resistant patient subgroup is characterized by high expression of the oncogenic TP73 isoform ΔNp73, exhibiting similarly poor outcomes as TP53-mutant AML. ΔNp73, which lacks a transcriptional activation domain but retains chromatin-binding properties, competes with TP53 for specific gene targets, thereby downregulating TP53 signaling. We demonstrate that the transcription factor CEBPA controls ΔNp73 expression in AML cells by binding to an intragenic enhancer region. Genetic or pharmacological inhibition of the transcriptional activity of CEBPA with guanfacine reduces ΔNp73 levels and restores drug sensitivity involving ferroptosis-mediated cell death, acting synergistically with venetoclax. Our study sheds light on a previously undercharacterized poor-risk subgroup of AML, which may support patient stratification and inform treatment considerations.

Keywords: AML PDX models; CEBPA; SREBP/SREBF; TP53-mutated AML; TP73; acute myeloid leukemia; drug resistance; ferroptosis; guanfacine; poor prognosis prediction.

MeSH terms

Bridged Bicyclo Compounds, Heterocyclic / pharmacology
CCAAT-Enhancer-Binding Proteins / genetics
CCAAT-Enhancer-Binding Proteins / metabolism
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics
Gene Expression Regulation, Leukemic
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / metabolism
Leukemia, Myeloid, Acute* / pathology
Mutation* / genetics
Protein Isoforms / genetics
Protein Isoforms / metabolism
Sulfonamides / pharmacology
Tumor Protein p73* / genetics
Tumor Protein p73* / metabolism
Tumor Suppressor Protein p53* / genetics
Tumor Suppressor Protein p53* / metabolism

Substances

Tumor Suppressor Protein p53
Protein Isoforms
Tumor Protein p73
CCAAT-Enhancer-Binding Proteins
Bridged Bicyclo Compounds, Heterocyclic
CEBPA protein, human
TP73 protein, human
TP53 protein, human
Sulfonamides
venetoclax