STAG2 mutations fine-tune the ALK-driven oncogenic program in ALK-positive anaplastic large cell lymphoma

ALK-positive Anaplastic Large Cell Lymphoma (ALK+ ALCL) is a rare yet aggressive T-cell lymphoma, most often characterized by the NPM1::ALK fusion. Because few somatic variants have been identified in ALK+ ALCL, we conducted paired whole-exome sequencing of patient tumors with matched normal tissue. Compared with previous studies, we identified a higher frequency of mutations in cohesin complex genes, mostly STAG2 variants (6/16) predicted to impair protein function. Immunohistochemistry confirmed loss of STAG2 in additional patient tumor samples. Using an original model of NPM1::ALK-driven lymphomagenesis that recapitulates early steps of ALK-driven transformation initiated in primary T lymphocytes, we demonstrated that STAG2 defect accelerates oncogenesis, enhancing early cell proliferation of ALK-positive cells. Single-cell RNA-seq revealed that STAG2 depletion accelerates the early acquisition of the major ALK+ ALCL hallmarks and concomitantly reduces the oncogene-induced senescence signature. Despite higher ALK expression and robust cell transformation, STAG2 depletion resulted in the attenuation of the global ALK+ ALCL transcriptional program. Importantly, STAG2 expression was found decreased upon NPM1::ALK induction, indicating intrinsic downregulation during transformation even without genomic mutations. We also successfully identified STAG2-low/ALK-high cells in both patient-derived tumors and PDX models. Functionally, STAG2-depleted cells exhibit increased cell adhesion and migration, alongside constitutive YAP1 activation and upregulation of adhesion molecule such as ALCAM and CD44 but also increased PD-L1. Overall, our findings reveal that STAG2 loss plays a key role during the earliest stages of ALK+ ALCL lymphomagenesis by promoting cell tolerance to NPM1::ALK expression and increasing permissiveness to malignant transformation while also impacting cell adhesion, migration.

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Publication Details

Journal
Blood
Published
2026-10-05
DOI
https://doi.org/10.1182/blood.2025032902
Primary Topic
Lymphoma Diagnosis and Treatment
Type
article
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article

STAG2 mutations fine-tune the ALK-driven oncogenic program in ALK-positive anaplastic large cell lymphoma

Erika Brunet, Vahid Asnafi, Alexandre Boullé, Josquin Moraly et al.
Blood
Lymphoma Diagnosis and Treatment
article

STAG2 mutations fine-tune the ALK-driven oncogenic program in ALK-positive anaplastic large cell lymphoma

Erika Brunet, Vahid Asnafi, Alexandre Boullé, Josquin Moraly, Bruno M. Tesson, Laurence Lamant, Layla Veleanu, Nicolas Cagnard, Fabienne Meggetto, Marion Le Grand, Leonardo Panunzi, Thomas Mercher, Patrick Revy, Zakia Aid, Maxime Heintzé, Lucile Couronné, Rosalie Borry, Carine Giovannangeli, Ludovic Lhermitte, Eddy Pasquier, Emilia Puig Lombardi, Alice Darchen, Didier Surdez, David Sibon, Charlotte Degoutte, Marie As, Loélia Babin, François Vilcot, Elisa Fabiole, Rania Sellami, Kevin Muller
article en

Abstract

ALK-positive Anaplastic Large Cell Lymphoma (ALK+ ALCL) is a rare yet aggressive T-cell lymphoma, most often characterized by the NPM1::ALK fusion. Because few somatic variants have been identified in ALK+ ALCL, we conducted paired whole-exome sequencing of patient tumors with matched normal tissue. Compared with previous studies, we identified a higher frequency of mutations in cohesin complex genes, mostly STAG2 variants (6/16) predicted to impair protein function. Immunohistochemistry confirmed loss of STAG2 in additional patient tumor samples. Using an original model of NPM1::ALK-driven lymphomagenesis that recapitulates early steps of ALK-driven transformation initiated in primary T lymphocytes, we demonstrated that STAG2 defect accelerates oncogenesis, enhancing early cell proliferation of ALK-positive cells. Single-cell RNA-seq revealed that STAG2 depletion accelerates the early acquisition of the major ALK+ ALCL hallmarks and concomitantly reduces the oncogene-induced senescence signature. Despite higher ALK expression and robust cell transformation, STAG2 depletion resulted in the attenuation of the global ALK+ ALCL transcriptional program. Importantly, STAG2 expression was found decreased upon NPM1::ALK induction, indicating intrinsic downregulation during transformation even without genomic mutations. We also successfully identified STAG2-low/ALK-high cells in both patient-derived tumors and PDX models. Functionally, STAG2-depleted cells exhibit increased cell adhesion and migration, alongside constitutive YAP1 activation and upregulation of adhesion molecule such as ALCAM and CD44 but also increased PD-L1. Overall, our findings reveal that STAG2 loss plays a key role during the earliest stages of ALK+ ALCL lymphomagenesis by promoting cell tolerance to NPM1::ALK expression and increasing permissiveness to malignant transformation while also impacting cell adhesion, migration.

Blood
Délégation Paris 5 (FR), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Paris Cité (FR), Institut Gustave Roussy (FR), Centre Hospitalier Universitaire Henri-Mondor (FR), Institut Necker Enfants Malades (FR), Centre de Recherches en Cancérologie de Toulouse (FR), Sorbonne Paris Cité (FR), Assistance Publique – Hôpitaux de Paris (FR), Institut universitaire du cancer de Toulouse Oncopole (FR), University Hospital of Zurich (CH), The Lymphoma Academic Research Organisation (FR), Muséum national d'Histoire naturelle (FR), Universitätsklinik Balgrist (CH), Hôpitaux Universitaires Henri-Mondor (FR), Centre de Recherche en Cancérologie de Marseille (FR), Institut des Maladies Génétiques Imagine (FR), Structure et Instabilité des Génomes (FR), Université Paris Descartes (FR)
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Lymphoma Diagnosis and Treatment
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