Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
Department of Hematology and Oncology, Federal Armed Forces Hospital Ulm, Ulm, Germany.
Blood Adv. 2022 Jan 25;6(2):637-651. doi: 10.1182/bloodadvances.2021005486.
Plasmablastic lymphoma (PBL) represents a clinically heterogeneous subtype of aggressive B-cell non-Hodgkin lymphoma. Targeted-sequencing studies and a single-center whole-exome sequencing (WES) study in HIV-positive patients recently revealed several genes associated with PBL pathogenesis; however, the global mutational landscape and transcriptional profile of PBL remain elusive. To inform on disease-associated mutational drivers, mutational patterns, and perturbed pathways in HIV-positive and HIV-negative PBL, we performed WES and transcriptome sequencing (RNA-sequencing) of 33 PBL tumors. Integrative analysis of somatic mutations and gene expression profiles was performed to acquire insights into the divergent genotype-phenotype correlation in Epstein-Barr virus-positive (EBV+) and EBV- PBL. We describe a significant accumulation of mutations in the JAK signal transducer and transcription activator (OSMR, STAT3, PIM1, and SOCS1), as well as receptor tyrosine-kinase RAS (ERBB3, NRAS, PDGFRB, and NTRK) pathways. We provide further evidence of frequent perturbances of NF-κB signaling (NFKB2 and BTK). Induced pathways, identified by RNA-sequencing, closely resemble the mutational profile regarding alterations accentuated in interleukin-6/JAK/STAT signaling, NF-κB activity, and MYC signaling. Moreover, class I major histocompatibility complex-mediated antigen processing and cell cycle regulation were significantly affected by EBV status. An almost exclusive upregulation of phosphatidylinositol 3-kinase/AKT/mTOR signaling in EBV+ PBL and a significantly induced expression of NTRK3 in concert with recurrent oncogenic mutations in EBV- PBL hint at a specific therapeutically targetable mechanism in PBL subgroups. Our characterization of a mutational and transcriptomic landscape in PBL, distinct from that of diffuse large B-cell lymphoma and multiple myeloma, substantiates the pathobiological independence of PBL in the spectrum of B-cell malignancies and thereby refines the taxonomy for aggressive lymphomas.
浆母细胞淋巴瘤（PBL）是一种具有临床异质性的侵袭性 B 细胞非霍奇金淋巴瘤。靶向测序研究和一项针对 HIV 阳性患者的单中心全外显子组测序（WES）研究最近揭示了几个与 PBL 发病机制相关的基因；然而，PBL 的全球突变景观和转录谱仍然难以捉摸。为了了解与疾病相关的突变驱动因素、突变模式和受扰途径，我们对 33 例 PBL 肿瘤进行了 WES 和转录组测序（RNA-seq）。对体细胞突变和基因表达谱进行综合分析，以深入了解 EBV 阳性（EBV+）和 EBV- PBL 中不同的基因型-表型相关性。我们描述了 JAK 信号转导和转录激活物（OSMR、STAT3、PIM1 和 SOCS1）以及受体酪氨酸激酶 RAS（ERBB3、NRAS、PDGFRB 和 NTRK）途径中显著积累的突变。我们进一步提供了 NF-κB 信号频繁受到干扰的证据（NFKB2 和 BTK）。RNA-seq 鉴定的诱导途径与白细胞介素 6/JAK/STAT 信号、NF-κB 活性和 MYC 信号中强调的改变的突变谱非常相似。此外，主要组织相容性复合体 I 类介导的抗原加工和细胞周期调节受到 EBV 状态的显著影响。EBV+ PBL 中几乎完全上调的磷脂酰肌醇 3-激酶/AKT/mTOR 信号和 EBV- PBL 中与反复发生的致癌突变协同诱导表达的 NTRK3 提示 PBL 亚组中存在特定的治疗靶点机制。我们对 PBL 中的突变和转录组图谱进行了表征，与弥漫性大 B 细胞淋巴瘤和多发性骨髓瘤不同，这证实了 PBL 在 B 细胞恶性肿瘤谱中的病理生物学独立性，并因此细化了侵袭性淋巴瘤的分类。
