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Updated: Aug 19, 2025
Flow-sorting and Exome Sequencing of the Reed-Sternberg Cells of Classical Hodgkin Lymphoma
Published on: June 10, 2017
JAK/STAT blockade reverses the malignant phenotype of Hodgkin and Reed-Sternberg cells
Sara Fernández1, Jose L Solórzano2, Eva Díaz1
1Translational Research Laboratory, MD Anderson Cancer Center Madrid, Madrid, Spain.
Abstract:
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.
Insights
Ruxolitinib inhibits the JAK/STAT pathway in classic Hodgkin lymphoma (cHL) cells, inducing apoptosis. This study identifies the G-CSF receptor (CSF3R) as a biomarker and reveals mechanisms of JAK/STAT blockade in cHL.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Constitutive activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a hallmark of classic Hodgkin lymphoma (cHL).
- Early-phase clinical trials are investigating the therapeutic potential of JAK/STAT pathway inhibitors in cHL.
- Limited understanding exists regarding the intricate biological effects of blocking this pathway in cHL.
Purpose of the Study:
- To investigate the biological consequences of JAK/STAT pathway inhibition in cHL cell models.
- To evaluate the efficacy of ruxolitinib, a JAK 1/2 inhibitor, in cHL.
- To identify potential biomarkers and elucidate the molecular mechanisms underlying JAK/STAT blockade in cHL.
Main Methods:
- Utilized ruxolitinib, a JAK 1/2 inhibitor, on cHL cell models.
- Employed whole-transcriptome analysis to identify gene expression changes.
- Conducted longitudinal gene expression analyses to map pathway alterations.
Main Results:
- Ruxolitinib demonstrated concentration- and time-dependent induction of apoptosis in cHL cells.
- Upregulation of the G-CSF receptor (CSF3R) was identified as a potential biomarker for JAK/STAT pathway overactivation.
- Gene expression analysis revealed distinct clusters of pathway modulation, including G2/M checkpoint and MHC-related genes, alongside downregulation of tumor-promoting inflammation signatures (JAK/STAT, IL-1, IL-4, IL-13, IL-17).
Conclusions:
- JAK/STAT inhibitors hold therapeutic promise for cHL.
- CSF3R emerges as a novel biomarker for JAK/STAT pathway activity in cHL.
- This study provides genetic and mechanistic insights into the effects of JAK/STAT inhibition in cHL.
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