RESUMO
BACKGROUND: Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether thrombotic risk stratification could be improved. We previously reported an association between thrombotic events and mutations in DTA genes (DNMT3A, TET2, and ASXL1). The objective of this study was to confirm this observation in a larger series of PV patients. METHODS: PV patients with a minimum follow-up of 3 years were recruited from 8 European centers. Medical history was searched for thrombotic event recorded at any time and next-generation sequencing carried out with a myeloid panel. Multivariable logistic regression evaluated the impact of variables on thrombotic risk. Kaplan-Meier thrombosis-free survival curves were compared by the log rank test. Associations in the total cohort were confirmed in a case-control study to exclude selection bias. RESULTS: Of the 136 patients recruited, 74 (56.1%) had a thrombotic event, with an incidence density of 2.83/100 person-years. In multivariable analysis, DTA mutation was a risk factor for thrombotic event, being predictive for shorter thrombosis-free survival in the whole cohort (p = 0.007), as well as in low-risk patients (p = 0.039) and older patients (p = 0.009), but not for patients with a prediagnostic event. A gender- and age-matched case-control study confirmed the increased risk of thrombotic event for PV patients with a DTA mutation. CONCLUSION: Our results support the use of molecular testing at diagnosis to help predict which PV patients are at higher risk of developing thrombosis.
Assuntos
DNA (Citosina-5-)-Metiltransferases , DNA Metiltransferase 3A , Proteínas de Ligação a DNA , Dioxigenases , Mutação , Policitemia Vera , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Trombose , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Trombose/genética , Fatores de Risco , Idoso , Policitemia Vera/genética , Policitemia Vera/complicações , Proteínas Repressoras/genética , Fatores Etários , Proteínas Proto-Oncogênicas/genética , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas de Ligação a DNA/genética , Estudos de Casos e Controles , Adulto , Europa (Continente)/epidemiologia , Incidência , Predisposição Genética para Doença , Medição de Risco , Estimativa de Kaplan-Meier , Idoso de 80 Anos ou maisRESUMO
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)-1ß 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-1ß 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.