JAK2V617F is the most recurrent genetic mutation in Philadelphia-negative chronic Myeloproliferative Neoplasms (MPNs). Since the JAK2 locus is located on Chromosome 9, we hypothesized that Chromosome 9 copy number abnormalities may be a disease modifier in JAK2V617F-mutant MPN patients. In this study, we identified a subset of MPN patients with partial or complete Chromosome 9 trisomy (+9p patients), who differ from JAK2V617F-homozygous MPN patients as they carry three JAK2 alleles as well as three copies of all neighboring gene loci, including CD274, encoding immunosuppressive Programmed death-ligand 1 (PD-L1) protein. Investigation of the clonal hierarchy revealed that the JAK2V617F occurs first, followed by +9p. Functionally, CD34+ cells from +9p MPN patients demonstrated increased clonogenicity, generating a greater number of primitive colonies, due to high OCT4 and NANOG expression, with knock-down of these genes leading to a genotype-specific decrease in colony numbers. Moreover, our analysis revealed increased PD-L1 surface expression in malignant monocytes from +9p patients, while analysis of the T cell compartment unveiled elevated levels of exhausted cytotoxic T cells. Overall, here we identify a distinct novel subgroup of MPN patients, who feature a synergistic interplay between +9p and JAK2V617F that shapes immune escape characteristics and increased stemness in CD34+ cells.

JAK2V617F 是费城阴性慢性骨髓增生性肿瘤 (MPN) 中最常见的基因突变。由于JAK2基因座位于 9 号染色体上，我们假设 9 号染色体拷贝数异常可能是 JAK2V617F 突变 MPN 患者的疾病调节剂。在这项研究中，我们鉴定了一部分具有部分或完全 9 号染色体三体性的 MPN 患者（+9p 患者），他们与 JAK2V617F 纯合性 MPN 患者不同，因为他们携带三个JAK2等位基因以及所有邻近基因位点的三个拷贝，包括CD274 ，编码免疫抑制程序性死亡配体 1 (PD-L1) 蛋白。对克隆层次结构的研究表明，JAK2V617F 首先出现，然后是 +9p。在功能上，来自+9p MPN患者的CD34+细胞表现出增加的集落形成性，由于OCT4和NANOG的高表达而产生更多数量的原始集落，敲低这些基因导致集落数量的基因型特异性减少。此外，我们的分析显示 +9p 患者的恶性单核细胞中 PD-L1 表面表达增加，而 T 细胞区室分析揭示了耗尽的细胞毒性 T 细胞水平升高。总体而言，我们在此确定了 MPN 患者的一个独特的新亚组，其特征是 +9p 和 JAK2V617F 之间存在协同相互作用，从而形成免疫逃逸特征并增加 CD34+ 细胞的干性。