Browsing by Subject "Anakinra"

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    NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy
    (Cell Press, 2023-12-19) 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; Bioquímica y Biología Molecular B e Inmunología
    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.