miR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression risk.
F Ferrer-MarínA B ArroyoB BellosilloE J CuencaL ZamoraJ M Hernández-RivasJuan Carlos Carlos Hernández-BoludaC Fernandez-RodriguezE LuñoC García HernandezA KerguelenD V Fiallo-SuárezM T Gómez-CasaresR AyalaP VélezC BoquéV García-GutierrezB ArrizabalagaN EstradaR CifuentesI ArcasA M de Los Reyes-GarcíaC BessesV VicenteA Alvarez-LarránR Teruel-MontoyaR González-ConejeroC Martíneznull nullPublished in: Leukemia (2020)
Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a-/- mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.
Keyphrases
- end stage renal disease
- cell proliferation
- risk factors
- newly diagnosed
- long non coding rna
- chronic kidney disease
- ejection fraction
- oxidative stress
- computed tomography
- long noncoding rna
- free survival
- type diabetes
- magnetic resonance imaging
- poor prognosis
- signaling pathway
- metabolic syndrome
- patient reported outcomes
- gene expression
- high grade
- inflammatory response
- genome wide
- contrast enhanced
- positron emission tomography
- diabetic rats