A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma
A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma
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DOI：
10.1158/0008-5472.can-20-2425
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发表时间：
2020-12-01
期刊：
影响因子：
11.2
通讯作者：
Yamamoto, Tetsuya
中科院分区：
文献类型：
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作者：
Tateishi, Kensuke;Miyake, Yohei;Yamamoto, Tetsuya
原发性中枢神经系统淋巴瘤(PCNSL)是一种孤立的中枢神经系统淋巴瘤，尽管进行了密集的化疗，但预后很差。最近的基因组分析发现，在免疫功能正常的PCNSL中，MYD88和CD79B基因高度重复突变，而LMP1激活通常在EB病毒(EBV)阳性的PCNSL中观察到。然而，缺乏具有临床代表性的临床前模型阻碍了我们对遗传异常驱动PCNSL疾病表型的致病机制的理解。在这里，我们从免疫活性和EBV阳性的PCNSL和继发性CNSL活检标本中建立了12个患者来源的原位异种移植(PDX)模型。PDX忠实地保留了其表型、代谢和遗传特征，与免疫功能正常患者PCNSL中存在的MYD88和CD79B突变100%一致。这些模型表明，在免疫活性PCNSL和EBV阳性PCNSL中，分别由突变的MYD88/CD79B或PIN1过度激活的LMP1共同驱动的RELA/P65-己糖激酶2信号轴具有收敛的功能依赖性。值得注意的是，免疫活性和EBV阳性的PCNSL使用的独特的分子变化会聚在一起，解除对relA/p65表达的调控，并驱动糖酵解，这对脑内肿瘤的进展和FDG-PET成像特征至关重要。这一关键信号轴的遗传和药物抑制在体外和体内都有效地抑制了PCNSL的生长。这些患者衍生的模型为预测临床化疗疗效提供了一个平台，并为PCNSL的发病机制提供了关键的见解，加速了这种侵袭性疾病的治疗发现。意义：一组临床相关的CNSL异种移植确定了高活性的RelA/p65-己糖激酶2信号轴是进展的驱动力和潜在的治疗靶点，并提供了一个基础的临床前平台。
Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein-Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/ CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease.Significance: A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform.