Myeloproliferative neoplasms (MPN) are chronic stem cell disorders characterized by enhanced proliferation of myeloid cells, immune deregulation, and drug resistance. JAK2 somatic mutations drive the disease in 50–60% and CALR mutations in 25–30% of cases. Published data suggest that JAK2-V617F-mutated MPN cells express the resistance-related checkpoint PD-L1. By applying RNA-sequencing on granulocytes of 113 MPN patients, we demonstrate that PD-L1 expression is highest among polycythemia vera patients and that PD-L1 expression correlates with JAK2-V617F mutational burden (R = 0.52; p < .0001). Single nucleotide polymorphism (SNP) arrays showed that chromosome 9p uniparental disomy (UPD) covers both PD-L1 and JAK2 in all MPN patients examined. MPN cells in JAK2-V617F-positive patients expressed higher levels of PD-L1 if 9p UPD was present compared to when it was absent (p < .0001). Moreover, haplotype-based association analyses provided evidence for germline genetic factors at PD-L1 locus contributing to MPN susceptibility independently of the previously described GGCC risk haplotype. We also found that PD-L1 is highly expressed on putative CD34⁺CD38⁻ disease-initiating neoplastic stem cells (NSC) in both JAK2 and CALR-mutated MPN. PD-L1 overexpression decreased upon exposure to JAK2 blockers and BRD4-targeting agents, suggesting a role for JAK2-STAT5-signaling and BRD4 in PD-L1 expression. Whether targeting of PD-L1 can overcome NSC resistance in MPN remains to be elucidated in forthcoming studies.

中文翻译：

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PD-L1 过表达与 JAK2-V617F 突变负荷相关，并且与骨髓增殖性肿瘤中的 9p 单亲二体性相关

骨髓增生性肿瘤 (MPN) 是一种慢性干细胞疾病，其特征是骨髓细胞增殖增强、免疫失调和耐药性。JAK2体细胞突变导致 50-60% 的疾病和CALR突变导致 25-30% 的病例。已发表的数据表明JAK2 -V617F 突变的 MPN 细胞表达与耐药性相关的检查点 PD-L1。通过对 113 名 MPN 患者的粒细胞进行 RNA 测序，我们证明 PD-L1 表达在真性红细胞增多症患者中最高，并且 PD-L1 表达与JAK2 -V617F 突变负荷相关（R  = 0.52；p < .0001)。单核苷酸多态性 (SNP) 阵列显示，染色体 9p 单亲二体性 (UPD)在所有检查的 MPN 患者中均涵盖PD-L1和JAK2 。如果存在 9p UPD，则与不存在时相比， JAK2 -V617F 阳性患者的MPN 细胞表达更高水平的 PD-L1 ( p  < .0001)。此外，基于单倍型的关联分析为PD-L1基因座的种系遗传因素提供了证据，这些因素导致 MPN 易感性​​独立于先前描述的 GGCC 风险单倍型。我们还发现 PD-L1在两种JAK2中推定的 CD34 ⁺ CD38 ^-疾病起始肿瘤干细胞 (NSC)上高度表达和CALR突变的 MPN。暴露于 JAK2 阻滞剂和 BRD4 靶向剂后，PD-L1 过表达降低，表明 JAK2-STAT5 信号传导和 BRD4 在 PD-L1 表达中的作用。靶向 PD-L1 是否可以克服 MPN 中的 NSC 耐药性仍有待在即将进行的研究中阐明。