JAK/STAT blockade reverses the malignant phenotype of Hodgkin and Reed-Sternberg cells.

Constitutive activation of the JAK/STAT pathway is a common phenomenon in classic Hodgkin lymphoma (cHL). The clinical potential of anti-JAK/STAT therapy is being explored in early-stage clinical trials. Notwithstanding, very little information is available about the complex biological consequences...

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Detalles Bibliográficos
Autores: Fernández, Sara, Solórzano, Jose L, Díaz, Eva, Menéndez, Victoria, Maestre, Maestre L, Palacios, Sara, López, Mar, Colmenero, Argentina, Estévez, Mónica, Montalbán, Carlos, Martínez, Ángel, Roncador, Giovanna, García, Juan F
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/18925
Acceso en línea:http://hdl.handle.net/20.500.12105/18925
Access Level:acceso abierto
Palabra clave:Reed-Sternberg Cells
Hodgkin Disease
Humans
Signal Transduction
Janus Kinases
STAT Transcription Factors
Phenotype
Descripción
Sumario:Constitutive activation of the JAK/STAT pathway is a common phenomenon in classic Hodgkin lymphoma (cHL). The clinical potential of anti-JAK/STAT therapy is being explored in early-stage clinical trials. Notwithstanding, very little information is available about the complex biological consequences of this blockade. Here, we investigated the effects of JAK/STAT pharmacological inhibition on cHL cell models using ruxolitinib, a JAK 1/2 inhibitor that induces apoptosis by concentration- and time-dependent mechanisms. An unbiased whole-transcriptome approach identified expression of the anti-GCSF receptor (CSF3R) as a potential surrogate biomarker of JAK/STAT overactivation. In addition, longitudinal gene expression analyses provided further mechanistic information about pertinent biological pathways involved, including 37 gene pathways distributed in 3 main clusters: cluster 1 was characterized by upregulation of the G2/M checkpoint and major histocompatibility complex-related clusters; 2 additional clusters (2 and 3) showed a progressive downregulation of the tumor-promoting inflammation signatures: JAK/STAT and interleukin 1 (IL-1)/IL-4/IL-13/IL-17. Together, our results confirm the therapeutic potential of JAK/STAT inhibitors in cHL, identify CSF3R as a new biomarker, and provide supporting genetic data and mechanistic understanding.

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