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Published on: October 26, 2017
miR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression
F Ferrer-Marín1,2,3, A B Arroyo4, B Bellosillo5
1Hospital Morales Meseguer, Centro Regional de Hemodonación, IMIB-Arrixaca, Murcia, Spain. fferrermarin@gmail.com.
Abstract:
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.
Insights
A specific genetic marker (rs2431697 TT genotype) predicts myelofibrosis progression in myeloproliferative neoplasms. This finding offers a new way to identify patients at risk for this serious disease.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- Myelofibrosis (MF) is a serious complication of polycythemia vera (PV) and essential thrombocythemia (ET), significantly reducing survival.
- Inflammation, mediated by NF-κB signaling, plays a crucial role in the progression of myeloproliferative neoplasms (MPNs) to advanced disease.
- MicroRNA-146a (miR-146a) acts as a negative regulator of NF-κB signaling, potentially influencing MPN development and progression.
Purpose of the Study:
- To investigate the role of specific miR-146a genetic variants (rs2910164 and rs2431697) in the susceptibility and progression of MPNs.
- To determine if the rs2431697 polymorphism is an independent predictor of progression to myelofibrosis.
- To explore the association between the rs2431697 genotype, inflammatory markers, and the development of an MF-like phenotype.
Main Methods:
- Genotyping of rs2910164 and rs2431697 in 967 MPN patients (PV, ET, MF) and 600 controls.
- Survival analysis (MF-free survival) in a cohort of 232 PV/ET patients followed for 8.5 years.
- Measurement of plasma inflammatory cytokines and assessment of Stat3 activity in miR-146a knockout mice.
Main Results:
- The rs2431697 TT genotype was significantly associated with MF, particularly post-PV/ET MF (HR=1.5, p<0.05).
- Patients with the TT genotype had a shorter MF-free survival compared to CC+CT genotypes (p=0.01).
- Multivariate analysis confirmed the TT genotype as an independent predictor of MF progression, with elevated plasma inflammatory cytokines observed in TT individuals. MiR-146a-/- mice exhibited increased Stat3 activity and an MF-like phenotype.
Conclusions:
- The rs2431697 TT genotype serves as an early predictor of myelofibrosis progression, independent of JAK2V617F allele burden.
- Reduced miR-146a expression, potentially due to the rs2431697 TT genotype, contributes to the MF phenotype by enhancing Stat3 signaling.
- These findings highlight the genetic and inflammatory interplay in MPN progression and identify a potential biomarker for risk stratification.
