染色体9p三体增加干细胞克隆潜能并促进JAK2突变骨髓增生异常症中的T细胞耗竭

Chromosome 9p trisomy increases stem cells clonogenic potential and fosters T-cell exhaustion in JAK2-mutant myeloproliferative neoplasms

LEUKEMIA

影响因子:13.4

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,

DOI: 10.1038/s41375-024-02373-w

摘要

JAK2V617F是Philadelphia阴性慢性骨髓增生异常症（MPNs）中最常见的遗传突变。由于JAK2位于第9号染色体上，我们假设染色体9的拷贝数异常可能是JAK2V617F突变MPN患者的疾病修饰因素。在本研究中，我们鉴定出一组部分或完全染色体9三体(+9p)患者的MPN患者，他们与JAK2V617F纯合子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座的三个拷贝，包括编码免疫抑制性程序性死亡配体1（PD-L1）的CD274。克隆层次结构的研究显示，JAK2V617F先发生，然后是+9p。从功能上看，来自+9p MPN患者的CD34+细胞表现出增强的克隆形成能力，生成更多的原始菌落，这归因于OCT4和NANOG的高表达，敲低这些基因导致基因型特异性地减少菌落数量。此外，我们的分析显示，+9p患者的恶性单核细胞表面PD-L1表达增加，而T细胞亚群分析揭示耗竭的细胞毒性T细胞水平升高。总体而言，本研究鉴定出一个具有独特特征的新型MPN亚组，其特征是+9p与JAK2V617F之间的协同作用，塑造免疫逃逸特征并增强CD34+细胞的干性。

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.