Ectopic PD-L1 expression in JAK2 (V617F) myeloproliferative neoplasm patients is mediated via increased activation of ST
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RESEARCH ARTICLE
Ectopic PD‑L1 expression in JAK2 (V617F) myeloproliferative neoplasm patients is mediated via increased activation of STAT3 and STAT5 Sameer Ahamd Guru1 · Mamta P. Sumi2 · Ab Rashid Mir3 · Ajaz Ahmad Waza4 · Musadiq Ahmad Bhat5 · Mariyam Zuberi6 · Promod Lali7 · Alpana Saxena7 Received: 27 January 2020 / Accepted: 24 April 2020 © Japan Human Cell Society 2020
Abstract Escalated PD-L1 expression has been identified during malignant transformation in a number of cancer types and helps cancer cells escape an effective anti-tumor immune response. The mechanisms underlying escalated production of PD-L1 in many cancers, however, are still far from clear. We studied PD-L1, STAT3 and STAT5 mRNA expression using qRT-PCR in 72 BCR/ABL1 negative myeloproliferative neoplasm (MPN) patients (39 polycythemia vera and 33 essential thrombocythemia). Furthermore, phosphorylation status of STAT3 and STAT5 was studied using immunoblotting in the same patients. All MPN patients were first screened for JAK2 (V617F) mutation by tetra-primer ARMS-PCR, followed by quantification of JAK2 (V617F) mutation burden in all V617F positive MPN patients by ASO-PCR. Patients were screened for BCR/ABL1 fusion gene transcripts to rule out Ph positive status. Our findings showed that mRNA levels of PD-L1 and STAT3 were significantly higher in JAK2 (V617F) MPN patients, while as STAT5 was insignificantly upregulated. STAT3 and STAT5 phosphorylation was seen to be higher in JAK2 (V617F) MPN patients compared to the JAK2 (WT) patients. Upregulation of PD-L1, STAT3 and STAT5 was significantly associated with JAK2 (V617F) percentage in MPN patients. PD-L1, STAT3 and STAT5 expression significantly and positively correlated with JAK2 (V617F) allele burden. In addition, significant coexpression of PD-L1 with STAT3 and STAT5 was observed in MPN patients. In summary, JAK2 (V617F) mutation is accompanied by increased PD-L1 expression and this PD-L1 over expression is mediated by JAK2 (V617F) mainly through STAT3, while as STAT5 may play a minor role. Graphic abstract
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Keywords Myeloproliferative neoplasms · Polycythemia vera · Essential thrombocythemia · JAK2 (V617F) · Programmed death ligand 1
Introduction Programmed death ligand 1 (PD-L1) also called CD274 or B7 homolog is a transmembrane protein that is found on active T cells, monocytes, thrombocytes and plays an important role in an effective immune response [1]. The first characterized ligand of co-inhibitory receptor PD-1 is PD-L1 and is encoded by PD-L1 gene located on chromosome 9p24.1 and spans approximately 17.6 kb [2]. The signal from PD-L1 is received by its receptor PD-1 and transmitted to downstream cascade. The activation of PD-1 and PD-L1 signalling leads to exhaustion of T cells and diminished immune response initiated by them. The hypothesis that PD-L1 expression is increased in malignant cells has been an important subject of research in the recent past. I
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