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ΔNp73 isoform defines a TP53-mutant-like poor-risk subgroup of acute myeloid leukemia
Diego A Pereira-Martins1, Cesar Ortiz2, Isabel Weinhäuser3
1Department 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.
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.
Insights
A subset of acute myeloid leukemia (AML) patients resistant to treatment overexpresses the oncogenic ΔNp73. Inhibiting CEBPA with guanfacine reduces ΔNp73, restoring drug sensitivity and improving outcomes in AML.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- A significant subgroup of acute myeloid leukemia (AML) patients exhibits resistance to standard therapies.
- The molecular mechanisms driving this treatment refractoriness in AML remain largely undefined.
Purpose of the Study:
- To investigate the molecular underpinnings of treatment resistance in a specific AML subgroup.
- To identify potential therapeutic targets for overcoming resistance in AML.
Main Methods:
- Multi-omics analysis to characterize resistant AML patient subgroups.
- Investigation of the role of TP73 isoforms, specifically ΔNp73.
- Analysis of CEBPA binding and regulation of ΔNp73 expression.
- Assessment of CEBPA inhibition using guanfacine and its effect on drug sensitivity, ferroptosis, and venetoclax synergy.
Main Results:
- High expression of the oncogenic TP73 isoform ΔNp73 characterizes a refractory AML subgroup with poor prognosis.
- ΔNp73 downregulates TP53 signaling by competing for gene targets.
- The transcription factor CEBPA regulates ΔNp73 expression via an intragenic enhancer.
- Inhibition of CEBPA transcriptional activity with guanfacine reduces ΔNp73 levels, restores drug sensitivity, and induces ferroptosis-mediated cell death.
- Guanfacine acts synergistically with venetoclax in resistant AML cells.
Conclusions:
- ΔNp73 is a key driver of treatment resistance in a subset of AML patients.
- Targeting CEBPA-mediated ΔNp73 expression with agents like guanfacine offers a potential therapeutic strategy for refractory AML.
- This research identifies a new poor-risk AML subgroup and suggests novel treatment approaches involving CEBPA inhibition and venetoclax.
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