NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy
Laura Hurtado‐Navarro, Ernesto José Cuenca‐Zamora, Lurdes Zamora, Beatríz Bellosillo, Esperanza Such, Eva Soler‐Espejo, Helios Martínez‐Banaclocha, Jesús María Hernández‐Rivas, Javier Marco, L. Martínez‐Alarcón, Lola Linares-Latorre, Sara García-Ávila, Paula Amat-Martínez, Teresa González, Montserrat Arnán, Helena Pomares-Marín, Gonzalo Carreño‐Tarragona, Tzu Hua Chen‐Liang, M. Herranz, Carlos García-Palenciano, María Luz Morales, Andrés Jerez, Marı́a Luisa Lozano, Raúl Teruel‐Montoya, Pablo Pelegrı́n, Francisca Ferrer‐Marín
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 cell 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 KRAS G12D mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves 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.