%0 Journal Article
%T NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy.
%A Hurtado-Navarro L
%A Cuenca-Zamora EJ
%A Zamora L
%A Bellosillo B
%A Such E
%A Soler-Espejo E
%A Martínez-Banaclocha H
%A Hernández-Rivas JM
%A Marco-Ayala J
%A Martínez-Alarcón L
%A Linares-Latorre L
%A García-Ávila S
%A Amat-Martínez P
%A González T
%A Arnan M
%A Pomares-Marín H
%A Carreño-Tarragona G
%A Chen-Liang TH
%A Herranz MT
%A García-Palenciano C
%A Morales ML
%A Jerez A
%A Lozano ML
%A Teruel-Montoya R
%A Pelegrín P
%A Ferrer-Marín F
%J Cell Rep Med
%V 4
%N 12
%D 2023 12 19
%M 38118408
%F 16.988
%R 10.1016/j.xcrm.2023.101329
%X 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 KRASG12D 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.