Page 225 - Haematologica Vol. 107 - September 2022

LETTER TO THE EDITOR
consequences of a constitutively activated JAK3 in NK-cell neoplasms, and its role in the occurrence of hemophago- cytic syndrome. By reproducing an animal model of ag- gressive NKTCL with the features of hemophagocytic syndrome, we found evidence that JAK3 deregulation in NKTCL provides a growth advantage to malignant cells,3,4 but also leads to an excessive production of interferon-γ, accounting for the systemic manifestations associated with NKTCL, such as hemophagocytic syndrome.11,12 Given that deregulated JAK3 is a common feature in NKTCL, our findings provide an explanation for the high prevalence of hemophagocytic syndrome reported in advanced NKTCL.13 Notably, the physiological regulation of interferon-γ secre- tion was related to multiple signaling proteins, including those in the STAT family and PI3-kinase and MAP-kinase pathways,14,15 and their constitutive activation in the pres- ence of deregulated JAK3 is in accordance with our model. An excessive production of interferon-γ, in turn, activates macrophages that release tumor necrosis factor-a. The conjunction of both cytokines accounts for the usual fea- tures of hemophagocytic syndrome, including fever and wasting, acute cytopenia, hyperferritinemia, hypertriglyce- ridemia, hyponatremia and hypofibrinogenemia.10
The crucial role of deregulated JAK3 in the pathophysiol- ogy of NKTCL, accounting for both growth advantage and excessive interferon-γ secretion, but also invasiveness through an amoeboid, matrix metalloproteinase-indepen- dent mechanism,3 makes this oncogenic protein target- able with specific inhibitors already approved for the treatment of inflammatory diseases.
Authors
Adrien Picod,1* Suella Martino,1* Pascale Cervera,2* Gregory Manuceau,1 Marc Arca,1 Monica Wittner,1 YanYan Zhang,1 He Liang,1 Florian Beghi,1 Eric Solary,1 Fawzia Louache1,3,4 and Paul Coppo1,5
1Inserm U1287, Gustave Roussy Institute, Villejuif; 2Service d’Anatomopathologie, Assistance Publique - Hôpitaux de Paris (AP- HP), Sorbonne Université, Paris; 3Université Paris-Sud, Orsay; 4French National Center for Scientific Research (CNRS) Research
References
1. Bigenwald C, Fardet L, Coppo P, et al. A comprehensive analysis of lymphoma-associated haemophagocytic syndrome in a large French multicentre cohort detects some clues to improve prognosis. Br J Haematol. 2018;183(1):68-75.
2. Wang H, Fu BB, Gale RP, Liang Y. NK-/T-cell lymphomas. Leukemia. 2021;35(9):2460-2468.
3. Bouchekioua A, Scourzic L, de Wever O, et al. JAK3 deregulation by activating mutations confers invasive growth advantage in
Group (GDR) 3697 MicroNiT and 5Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT), Service d’Hématologie, AP-HP - Sorbonne Université, Paris, France.
*AP, SM and PC contributed equally as co-first authors.
Correspondence:
P. COPPO - paul.coppo@aphp.fr
https://doi.org/10.3324/haematol.2021.280349
Received: November 15, 2021. Accepted: April 22, 2022. Prepublished: May 5, 2022.
©2022 Ferrata Storti Foundation Published under a CC BY-NC license
Disclosures
No conflicts of interest to disclose.
Contributions
AP performed experiments on mice and wrote the first version of the manuscript. SM, GM and MA performed experiments in vitro. MW, YZ, HL and FB performed experiments on mice. PCe performed histopathological analyses. ES, FL and PCo designed experiments and supervised the work.
Acknowledgments
The authors would like to thank Sébastien Malinge and Thomas Mercher, who provided JAK3WT and JAK3A573V retroviral vectors, and Sophie Ezine who provided Rag2-/- mice. Figures describing protocols were created using Servier Medical Art (smart.servier.com).
Funding
This work was funded in part by grants from the following institutions: Fondation pour la Recherche Médicale (FRM), Association pour la Recherche contre le Cancer, and Société d’Hématologie et d’Immunologie Pédiatrique (SHIP).
Data-sharing statement
Data from the current work are available on request.
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