Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma
Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma
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DOI：
10.1182/blood-2010-05-282780
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发表时间：
2010-10-28
期刊：
影响因子：
20.3
通讯作者：
Shipp, Margaret A.
中科院分区：
文献类型：
--
作者：
Green, Michael R.;Monti, Stefano;Shipp, Margaret A.
经典型霍奇金淋巴瘤（cHL）和纵隔大B细胞淋巴瘤（MLBCL）是具有某些共同临床、组织学和分子特征的淋巴系统恶性肿瘤。原发性cHL和MLBCL在炎性浸润物中包括可变数量的恶性细胞，表明这些肿瘤逃避免疫监视。在此，我们将高分辨率拷贝数数据与转录谱相结合，并将免疫调节基因PD-L1和PD-L2确定为HL和MLBCL细胞系中9p24.1扩增峰的关键靶标。我们将这些发现扩展到激光捕获显微切割的原代霍奇金Reed-Sternberg细胞和原代MLB-CL，发现程序性细胞死亡-1（PD-1）配体/9p24.1扩增仅限于结节硬化性HL，这是与MLBCL关系最密切的cHL亚型。使用定量免疫组织化学方法，我们记录了原发性肿瘤中9p24.1拷贝数和PD-1配体表达之间的关联。在cHL和MLBCL中，延伸的9p24.1扩增区域还包括Janus激酶2（JAK 2）基因座。值得注意的是，JAK 2扩增增加了蛋白质表达和活性，特异性诱导PD-1配体转录并增强了对JAK 2抑制的敏感性。因此，9p24.1扩增是一种疾病特异性结构改变，其增加了PD-1配体的基因剂量和JAK 2对其的诱导，将PD-1途径和JAK 2定义为互补的合理治疗靶点。（血。2010;116（17）：3268-3277）
Classical Hodgkin lymphoma (cHL) and mediastinal large B-cell lymphoma (MLBCL) are lymphoid malignancies with certain shared clinical, histologic, and molecular features. Primary cHLs and MLBCLs include variable numbers of malignant cells within an inflammatory infiltrate, suggesting that these tumors escape immune surveillance. Herein, we integrate high-resolution copy number data with transcriptional profiles and identify the immunoregulatory genes, PD-L1 and PD-L2, as key targets at the 9p24.1 amplification peak in HL and MLBCL cell lines. We extend these findings to laser-capture microdissected primary Hodgkin Reed-Sternberg cells and primary MLB-CLs and find that programmed cell death-1 (PD-1) ligand/9p24.1 amplification is restricted to nodular sclerosing HL, the cHL subtype most closely related to MLBCL. Using quantitative immunohistochemical methods, we document the association between 9p24.1 copy number and PD-1 ligand expression in primary tumors. In cHL and MLBCL, the extended 9p24.1 amplification region also included the Janus kinase 2 (JAK2) locus. Of note, JAK2 amplification increased protein expression and activity, specifically induced PD-1 ligand transcription and enhanced sensitivity to JAK2 inhibition. Therefore, 9p24.1 amplification is a disease-specific structural alteration that increases both the gene dosage of PD-1 ligands and their induction by JAK2, defining the PD-1 pathway and JAK2 as complementary rational therapeutic targets. (Blood. 2010;116(17):3268-3277)