NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy

• Published in: Cell reports. Medicine 2023-12, Vol.4 (12), p.101329-101329, Article 101329
• Main Authors: Hurtado-Navarro, Laura, Cuenca-Zamora, Ernesto José, Zamora, Lurdes, Bellosillo, Beatriz, Such, Esperanza, Soler-Espejo, Eva, Martínez-Banaclocha, Helios, Hernández-Rivas, Jesús M, Marco-Ayala, Javier, Martínez-Alarcón, Laura, Linares-Latorre, Lola, García-Ávila, Sara, Amat-Martínez, Paula, González, Teresa, Arnan, Montserrat, Pomares-Marín, Helena, Carreño-Tarragona, Gonzalo, Chen-Liang, Tzu Hua, Herranz, María T, García-Palenciano, Carlos, Morales, María Luz, Jerez, Andrés, Lozano, María L, Teruel-Montoya, Raúl, Pelegrín, Pablo, Ferrer-Marín, Francisca
• Format: Article
• Language: English
• Subjects: Humans; Inflammasomes - genetics; Inflammasomes - metabolism; Interleukin-1 - metabolism; Leukemia, Myelomonocytic, Chronic - drug therapy; Leukemia, Myelomonocytic, Chronic - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Symptom Burden
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2023.101329

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 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.