Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
Am J Hematol. 2022 Apr;97(4):390-400. doi: 10.1002/ajh.26461. Epub 2022 Jan 21.
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.
骨髓增殖性肿瘤（MPN）是一种慢性干细胞疾病，其特征是髓系细胞增殖增强、免疫失调和耐药性。JAK2 体细胞突变驱动 50-60%的疾病，CALR 突变驱动 25-30%的疾病。已发表的数据表明，JAK2-V617F 突变的 MPN 细胞表达耐药相关检查点 PD-L1。通过对 113 例 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 突变负担相关（R=0.52；p<0.0001）。单核苷酸多态性（SNP）阵列显示，9p 单亲二体性（UPD）在所有检查的 MPN 患者中同时覆盖 PD-L1 和 JAK2。与不存在 9p UPD 相比，JAK2-V617F 阳性患者的 MPN 细胞中 PD-L1 表达水平更高（p<0.0001）。此外，基于单倍型的关联分析提供了证据，证明 PD-L1 基因座的种系遗传因素独立于先前描述的 GGCC 风险单倍型，有助于 MPN 的易感性。我们还发现，PD-L1 在 JAK2 和 CALR 突变的 MPN 中，假定的 CD34 CD38 疾病起始性肿瘤干细胞（NSC）上高度表达。PD-L1 过表达在暴露于 JAK2 阻滞剂和 BRD4 靶向药物后降低，表明 JAK2-STAT5 信号和 BRD4 在 PD-L1 表达中起作用。在即将进行的研究中，是否靶向 PD-L1 可以克服 MPN 中的 NSC 耐药性仍有待阐明。
