High Cell-free (cf)DNA in Patients with Myelofibrosis (MF) is Associated with Adverse Clinical Outcomes, Activation of the AIM2 Inflammasome and Elevated Levels of Inflammasome-Related Cytokine IL-18

DE LUCA G.; GOETTE NP.; LEV PR.; CAMACHO MF.; CASTRO RÍOS M.; SACKMAN F.; MOIRAGUI B.; CORTES GUERRIERI V.; CAULA V.; VERRI V.; BENDEK G.; CARRICONDO E; VICENTE A.; VARELA A.; VALLEJOS V.; GUTIERREZ MI; LARRIPA I.; MARTA RF.; GLEMBOTSKY, AC.; HELLER PG.

Montreal

Congreso; ISTH 2023 Congress of the International Society on Thrombosis and Haemostasis (ISTH), Montreal, Canada, 24-28 de Junio 2023; 2023

International Society of Thrombosis and Haemostasis

Background: Myelofibrosis is a myeloproliferative neoplasm associated withpoor outcome, caused by driver (JAK2/CALR/MPL) and high-risk mutationscoupled to a chronic inflammatory process. cfDNA consists of short DNAfragments present in the non-cellular blood fraction. It has pro-inflammatoryeffects being one of its targets the AIM2 inflammasome, responsible formaturation and release of IL-1β and IL-18.Aims: To assess whether cfDNA is useful as a biomarker for clinical outcomein MF and its contribution to the inflammatory state.Methods: cfDNA was measured by fluorometry, IL-18 and C-reactiveprotein (CRP) by ELISA and AIM2 by qPCR.Results: cfDNA was elevated in MF patients (n = 72) vs. controls(P < 0.0001). We also found high levels of IL-18, an inflammasomeproduct, in MF plasma (P < 0.0001), reflecting in vivo inflammasomeactivation. Close association was found between higher values of cfDNAand IL-18 and clinical complications, including cytopenias, constitutionalsymptoms, circulating blasts and shortened survival. High levels of bothinflammatory mediators were also associated with adverse mutationalprofile and higher-risk categories (DIPSS/MIPSS70 scores) (P < 0.0001).Correlation was found between cfDNA, IL-18, LDH, and inflammatorymarker CRP (P < 0.0001). Considering that monocytes are effectors of MFinflammation and that IL-18 correlated with monocyte counts, we assessedtheir contribution to systemic IL-18. Patient monocytes had increased AIM2expression (P < 0.0001) and released higher IL-18 upon AIM2 stimulationwith a synthetic DNA, (P < 0.01), indicating monocytes are a relevant sourceof IL-18 in MF. Both IL-18 and AIM2 were higher in JAK2V617F-positivepatients.Conclusion(s): Association between cfDNA and advanced disease suggestsits potential role as prognostic factor in MF. The novel finding of elevated IL18 reveals its involvement in MF cytokine network. Close correlationbetween cfDNA and systemic IL-18, together with enhanced monocyteAIM2 expression and function suggests cfDNA triggers inflammationthrough AIM2 inflammasome activation, revealing new players in MFinflammatory circuit.