Surface CD81 supports leukemia stem cell function and reveals a therapeutic vulnerability in acute myeloid leukemia

Relapse remains the leading cause of mortality in acute myeloid leukemia (AML), largely due to the persistence of therapy-resistant leukemia stem cells (LSCs). However, surface determinants that sustain LSC function and disease aggressiveness remain incompletely defined. Here, we identify the tetraspanin CD81 as a regulator of LSC function, progression and treatment resistance in AML. Analysis of retrospective patient cohorts revealed that high CD81 surface expression is associated with relapse and adverse clinical outcomes in non-core-binding factor AML. Functional studies demonstrated that elevated CD81 expression promotes chemoresistance and enhances leukemic engraftment in immunodeficient mouse models. In vivo gain- and loss-of-function approaches further established that CD81 drives increased leukemia burden and aggressive disease behavior. Notably, CD81 was enriched within LSC-containing subpopulations, where its expression supported LSC maintenance and resistance to chemotherapy. Mechanistically, CD81 promotes chemoresistance and leukemic aggressiveness through pathways linked to LAPTM4B-mediated STAT3 signaling and enhanced adhesion-dependent cellular interactions. These effects were accompanied by increased migration, invasion, and formation of filopodia-like membrane protrusions. Importantly, therapeutic immunotargeting of CD81 significantly reduced leukemic burden while exhibiting a manageable toxicity profile in preclinical models. Collectively, these findings establish CD81 as a clinically relevant surface marker associated with AML relapse and identify CD81-dependent signaling as a therapeutic vulnerability for targeting LSCs and preventing disease recurrence.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2026-04-21
DOI
https://doi.org/10.1038/s41392-026-02697-2
Primary Topic
Cell Adhesion Molecules Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Surface CD81 supports leukemia stem cell function and reveals a therapeutic vulnerability in acute myeloid leukemia

Nicolas Pottier, Antonino Bongiovanni, Adriana Pleșa, Claude Preudhomme et al.
Signal Transduction and Targeted Therapy
Cell Adhesion Molecules Research
article

Surface CD81 supports leukemia stem cell function and reveals a therapeutic vulnerability in acute myeloid leukemia

Nicolas Pottier, Antonino Bongiovanni, Adriana Pleșa, Claude Preudhomme, Adeline Barthélémy, Véronique Lisi, Christophe Roumier, Cyril Couturier, François Sevrin, Vincent‐Philippe Lavallée, Fanny Gonzales, Nihad Boukrout, Meyling Cheok, Céline Berthon, Nicolas Duployez, Soizic Houdiard, Konstantinos Geles, Djohana Laurent, Pauline Peyrouze, Thomas Boyer
article en

Abstract

Relapse remains the leading cause of mortality in acute myeloid leukemia (AML), largely due to the persistence of therapy-resistant leukemia stem cells (LSCs). However, surface determinants that sustain LSC function and disease aggressiveness remain incompletely defined. Here, we identify the tetraspanin CD81 as a regulator of LSC function, progression and treatment resistance in AML. Analysis of retrospective patient cohorts revealed that high CD81 surface expression is associated with relapse and adverse clinical outcomes in non-core-binding factor AML. Functional studies demonstrated that elevated CD81 expression promotes chemoresistance and enhances leukemic engraftment in immunodeficient mouse models. In vivo gain- and loss-of-function approaches further established that CD81 drives increased leukemia burden and aggressive disease behavior. Notably, CD81 was enriched within LSC-containing subpopulations, where its expression supported LSC maintenance and resistance to chemotherapy. Mechanistically, CD81 promotes chemoresistance and leukemic aggressiveness through pathways linked to LAPTM4B-mediated STAT3 signaling and enhanced adhesion-dependent cellular interactions. These effects were accompanied by increased migration, invasion, and formation of filopodia-like membrane protrusions. Importantly, therapeutic immunotargeting of CD81 significantly reduced leukemic burden while exhibiting a manageable toxicity profile in preclinical models. Collectively, these findings establish CD81 as a clinically relevant surface marker associated with AML relapse and identify CD81-dependent signaling as a therapeutic vulnerability for targeting LSCs and preventing disease recurrence.

Signal Transduction and Targeted TherapyVol. 11(1)
Université Claude Bernard Lyon 1 (FR), University of Geneva (CH), Centre National de la Recherche Scientifique (FR), Inserm (FR), Lyon College (US), Université de Lille (FR), Institut Pasteur de Lille (FR), Centre Hospitalier Universitaire Sainte-Justine (CA), Centre Hospitalier Universitaire de Lille (FR), Lille’s Cardiology Hospital (FR), Hospices Civils de Lyon (FR), Institut thématique Génétique, génomique et bioinformatique (FR), Centre de Recherche en Cancérologie de Lyon (FR), Hôpital Claude Huriez (FR), Université de Picardie Jules Verne (FR), HCL Technologies (India) (IN)
Université de Lille, Agence Nationale de la Recherche, Fondation ARC pour la Recherche sur le Cancer, Ligue Contre le Cancer, Institut National Du Cancer, National Cancer Institute
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