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

•CSF3R is identified as a biomarker of JAK/STAT constitutive activation in Hodgkin and Reed-Sternberg cells.•JAK/STAT blockade activates the G2/M checkpoint and MHC pathways and downregulates all the tumor-promoting inflammation signatures. [Display omitted] Constitutive activation of the JAK/STAT p...

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Published in:Blood advances 2023-08, Vol.7 (15), p.4135-4147
Main Authors: Fernández, Sara, Solórzano, Jose L., Díaz, Eva, Menéndez, Victoria, Maestre, Lorena, Palacios, Sara, López, Mar, Colmenero, Argentina, Estévez, Mónica, Montalbán, Carlos, Martínez, Ángel, Roncador, Giovanna, García, Juan F.
Format: Article
Language:English
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Lymphoid Neoplasia
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Summary:•CSF3R is identified as a biomarker of JAK/STAT constitutive activation in Hodgkin and Reed-Sternberg cells.•JAK/STAT blockade activates the G2/M checkpoint and MHC pathways and downregulates all the tumor-promoting inflammation signatures. [Display omitted] 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.
ISSN:2473-9529
2473-9537
DOI:10.1182/bloodadvances.2021006336