The <i>JAK2</i> 46/1 haplotype influences PD-L1 expression
Abstract
Abstract Although described more than a decade ago, the mechanism by which the JAK2 46/1 haplotype increases the risk of developing JAK2-mutated myeloproliferative neoplasms (MPNs) remains unexplained. Inflammation and immunity are linked to MPN development and thus could be relevant to the mechanism by which 46/1 mediates its effect. Here, we show that programmed death-1 receptor ligand (PD-L1) expression is elevated in 46/1 haplotype, both in healthy carriers and in CD34+ cells from patients with MPN. Using circular chromosome conformation capture, we observed that PD-L1 and the neighboring PD-L2 loci physically interact with JAK2 in a manner that differs between 46/1 and nonrisk haplotypes. CRISPR/Cas9 genome editing identified a region within JAK2 intron 2 that influences both JAK2 and PD-L1 expression. We suggest that increased PD-L1 expression may be relevant to the mechanism by which 46/1 leads to an increased inherited risk of developing MPN.
Article Details
Authors (13)
Gonzalo Carreño-Tarragona
1Hematology Department, Hospital Universitario 12 de Octubre, I+12, Centro Nacional de Investigaciones Oncológicas, Complutense University, Centro de Investigación Biomédica en Red de Oncología, Madrid, Spain
María Tiana
Raquel Rouco
Alejandra Leivas
1Hematology Department, Hospital Universitario 12 de Octubre, I+12, Centro Nacional de Investigaciones Oncológicas, Complutense University, Centro de Investigación Biomédica en Red de Oncología, Madrid, Spain
Jesús Victorino
4Functional Genomics Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
Roberto García-Vicente
4Department of Translational Hematology, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, Hospital 12 de Octubre - Centro Nacional de Investigaciones Oncológicas, CIBERONC, ES 28041, Madrid, Spain., Madrid, Spain
Andrew J. Chase
1Faculty of Medicine, University of Southampton, Southampton, United Kingdom
Andrea Maidana
2Tissue and Organ Homeostasis Program, Centro de Biología Molecular Severo Ochoa, Centro Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
William J. Tapper
1Faculty of Medicine, University of Southampton, Southampton, United Kingdom
Rosa Ayala
HOSPITAL 12 DE OCTUBRE, MADRID, Spain
Nicholas C. P. Cross
Joaquín Martínez-López
Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Complutense University of Madrid, Centro Nacional de Investigaciones Oncológicas, Madrid Institute of Cancer, Madrid
Miguel Manzanares