Publication: NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy
Authors
Hurtado-Navarro, Laura ; Cuenca-Zamora, Ernesto J ; Zamora, Lurdes ; Bellosillo, Beatriz ; Such, Esperanza ; Soler-Espejo, Eva ; Martínez-Banaclocha, Helios ; Hernández-Rivas, Jesus M. ; Marco-Ayala, Javier ; Martínez-Alarcón, Laura ; Linares-Latorre, Lola ; García-Ávila, Sara ; Amat-Martínez, Paula ; González, Teresa ; Arnan, Monserrat ; Pomares-Marín, Helena ; Carreño-Tarragona, Gonzalo ; Chen-Liang, Tzu Hua ; Herranz, Maria T. ; García-Palenciano, Carlos ; Morales, María Luz ; Jerez, Andrés ; Lozano, Maria L. ; Teruel-Montoya, Raul ; Ferrer-Marín, Francisca ; Pelegrín Vivancos, Pablo
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Publisher
Cell Press
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DOI
https://doi.org/10.1016/j.xcrm.2023.101329
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info:eu-repo/semantics/article
Description
© 2023 The Authors. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Cell Reports Medicine. To access the final edited and published work see https://doi.org/10.1016/j.xcrm.2023.101329
Abstract
Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cells proliferation and survival, and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1β release. Here we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1β release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRASG12D mutation using the IL-1 receptor blocker anakinra inhibit NLRP3 inflammasome activation, reduce monocyte count, and improve the patient’s clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.
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Citation
Cell Reports Medicine, 2023, Vol. 4, Issue 12 : 101329
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Este ítem está sujeto a una licencia Creative Commons. http://creativecommons.org/licenses/by-nc-nd/4.0/