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.
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Acknowledgements
This work was supported by Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER; grant no. PI18/0316; PI17/0051; and PI16/0153 to BB [2017SGR205]) and Fundación Séneca (19873/GERM/15; 20644/JLI/18). ABA and AMR-G have a research Fellowship from Sociedad Española de Trombosis y Hemostasia (SETH) and from Instituto de Salud Carlos III (FI18/0045), respectively. This study was partially funded by Novartis International (CINC424AES05T). The authors thank Humberto Gómez (Department of Epidemiology, Servicio Murciano de Salud, Murcia, Spain) for his assistance in invaluable help with the statistical analysis.
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ABA, BB, LZ, RTM, EJC, RC, AMR-G, and FFM collected the data and performed the molecular studies. BB and CFR performed the NGS studies. ABA, EJC, AMR-G, and FFM performed ELISAs and Luminex assay. IA performed histological studies. ABA, BB, LZ, AAL, JCHB, JMHR, RGC, and CM analyzed and interpreted the results and wrote the paper. ABA, BB, LZ, JCHB, JMHR, EL, CGH, AK, DVF-S, MTG-C, RA, CB, PV, VGG, BA, NE, RC, EJC, and RTM collected the data and approved the final version. FFM, RGC, and CM designed the study. ABA, EJC, RTM, and FFM performed the statistical analysis. All authors participated in drafting the paper and approved the final version of the paper for submission.
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This study was partially funded by Novartis International (CINC424AES05T).
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Ferrer-Marín, F., Arroyo, A.B., Bellosillo, B. et al. miR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression risk. Leukemia 34, 2648–2659 (2020). https://doi.org/10.1038/s41375-020-0767-3
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DOI: https://doi.org/10.1038/s41375-020-0767-3
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