9p染色体三体染色体增加了干细胞的克隆发育潜力，并促进了JAK2突变剂髓增生性肿瘤中的T细胞衰竭
Chromosome 9p trisomy increases stem cells clonogenic potential and fosters T-cell exhaustion in JAK2-mutant myeloproliferative neoplasms
影响因子:13.40000
分区:医学1区 Top / 血液学1区 肿瘤学2区
发表日期:2024 Oct
作者:
Chiara Carretta, Sandra Parenti, Matteo Bertesi, Sebastiano Rontauroli, Filippo Badii, Lara Tavernari, Elena Genovese, Marica Malerba, Elisa Papa, Samantha Sperduti, Elena Enzo, Margherita Mirabile, Francesca Pedrazzi, Anita Neroni, Camilla Tombari, Barbara Mora, Margherita Maffioli, Marco Mondini, Marco Brociner, Monica Maccaferri, Elena Tenedini, Silvia Martinelli, Niccolò Bartalucci, Elisa Bianchi, Livio Casarini, Leonardo Potenza, Mario Luppi, Enrico Tagliafico, Paola Guglielmelli, Manuela Simoni, Francesco Passamonti, Ruggiero Norfo, Alessandro Maria Vannucchi, Rossella Manfredini,
摘要
JAK2V617F是费城阴性慢性骨髓增生性肿瘤（MPN）中最复发的基因突变。由于JAK2基因座位于9号染色体上，因此我们假设9染色体拷贝数异常可能是JAK2V617F突变的MPN患者中的疾病修饰剂。 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.对克隆层次结构的研究表明，JAK2V617F首先发生，其次是 +9p。在功能上，来自 + 9p MPN患者的CD34 +细胞表现出增加的克隆性，由于高Oct4和Nanog表达而产生了更多的原始菌落，这些基因的敲低，导致菌落数量的基因型特异性下降。此外，我们的分析表明， +9p患者的恶性单核细胞中PD-L1表面表达增加，而对T细胞室的分析揭示了耗尽的细胞毒性T细胞水平升高。总体而言，在这里，我们确定了一个独特的新型MPN患者亚组，它们具有 + 9p和JAK2V617F之间的协同相互作用，该相互作用塑造了CD34 +细胞中免疫逃逸特性和增加的干性。
Abstract
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.