PD-L1 and JAK2 mRNA level in essential thrombocythaemia depends on the driver mutational status and the bone marrow fibrosis grade

Background: JAK-STAT pathway activation leads to an enhanced activity of the promoter of CD274 (PDL1) coding programmed death-1 receptor ligand (PD-L1), increased PD-L1 level and the immune escape of myeloproliferative neoplasms (MPN) cells. It has been postulated that the bone marrow failure, bone marrow myeloid metaplasia, and changes in the molecular characteristics of the malignant clone(s) during MPN outcome may influence the JAK2 and PDL1 gene expression. Aim: to evaluate the PDL1 mRNA and JAK2 mRNA level in molecularly defined essential thrombocythaemia (ET) patients (pts) during disease progression to post-ET- myelofibrosis (post-ET-MF). Methods: the study group consisted of 162 ET pts, including 30 diagnosed with post-ET-MF. Results: the JAK2V617F, CALR, and MPL mutations were found in 59.3%, 19.1%, and 1.2% of pts, respectively. The total JAK2 mRNA level (V617F+WT) did not differ according to the JAK2 haplotypeGGCC_46/1 or the type of driver defect. No copy-number alternations of the JAK2, PDL1, and PDCDL1G2 (PDL2) genes were found. The level of PD-L1 was significantly higher in the JAK2V617F than in the JAK2WT, CALR mutation-positive, and triple-negative pts. The PD-L1 mRNA level was weakly correlated with both the JAK2V617F variant allele frequency (VAF), and with the JAK2V617F allele mRNA level. The total JAK2 level in post-ET-MF pts was lower than in ET pts despite the lack of differences in the JAK2V617F VAF. In addition, the PD-L1 level was lower in post-ET-MF. The detailed analysis has shown that the decrease in JAK2 and PD-L1 mRNA levels depended on the bone marrow fibrosis grade. The PDL1 expression showed no difference in relation to the genotype of 46/1 haplotype, hemoglobin concentration, hematocrit value, leukocyte, and platelet counts. Conclusion: the study confirmed the correlation between the PD-L1 and JAK2 mRNA level in ET pts. The observed drop of the total JAK2 and PD-L1 levels during the ET progression to the post-ET-MF may reflect the changes in the JAK2V617F positive clone proliferative potential and the PD-L1 level related immunosuppressive effect. This decrease could explain the lack of efficacy of the pembrolizumab in patients with advanced post-ET-MF and post-polycythemia vera myelofibrosis which was recently reported.