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

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  • dc.contributor.author Hurtado Navarro, Laura
  • dc.contributor.author Bellosillo Paricio, Beatriz
  • dc.contributor.author García Ávila, Sara
  • dc.contributor.author Ferrer-Marín, Francisca
  • dc.date.accessioned 2024-10-08T06:26:28Z
  • dc.date.available 2024-10-08T06:26:28Z
  • dc.date.issued 2023
  • dc.description.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 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.
  • dc.description.sponsorship This work was supported by grants to P.P. from MCIN/AEI/10.13039/501100011033 (grant PID2020-116709RB-I00), Fundación Séneca (grants 20859/PI/18, 21897/PI/22, and 21081/PDC/19), the Instituto de Salud Carlos III (grants DTS21/00080 and AC22/00009), the EU Horizon 2020 project PlasticHeal (grant 965196), and grants from the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER) to F.F.-M. (PI21/00347). L.H.-N. was supported by Fellowship 21214/FPI/19 (Fundación Séneca, Región de Murcia, Spain). E.J.C.-Z. is supported by the Training of University Teachers Program (FPU18/03189). M.L.M. is supported by Next Generation EU grant (PMP21/00052). This study was approved by the Clinical Research Ethics Committee of the Hospital Universitario Morales-Meseguer (reference no. 07/19). All patients and donors provided written informed consent in accordance with the Declaration of Helsinki.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Hurtado-Navarro L, Cuenca-Zamora EJ, Zamora L, Bellosillo B, Such E, Soler-Espejo E, et al. NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy. Cell Rep Med. 2023 Dec 19;4(12):101329. DOI: 10.1016/j.xcrm.2023.101329
  • dc.identifier.doi http://dx.doi.org/10.1016/j.xcrm.2023.101329
  • dc.identifier.issn 2666-3791
  • dc.identifier.uri http://hdl.handle.net/10230/61345
  • dc.language.iso eng
  • dc.publisher Elsevier
  • dc.relation.ispartof Cell Rep Med. 2023 Dec 19;4(12):101329
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/965196
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-116709RB-I00
  • dc.rights © 2023 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.keyword CMML
  • dc.subject.keyword IL-1 blockers
  • dc.subject.keyword KRAS
  • dc.subject.keyword NLRP3 blockers
  • dc.subject.keyword NLRP3 inflammasome
  • dc.subject.keyword RAS mutations
  • dc.subject.keyword Anakinra
  • dc.subject.keyword Inflammation
  • dc.subject.keyword Myelodysplastic syndromes
  • dc.subject.keyword Myeloproliferative neoplasms
  • dc.title NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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