Institute of Hematology and Center for Hemato-Oncology Research, University and Hospital of Perugia, Perugia, Italy.
Departments of Systems Biology and Biomedical Informatics, Columbia University, New York, NY.
Blood. 2018 May 31;131(22):2454-2465. doi: 10.1182/blood-2017-11-814913. Epub 2018 Apr 12.
Dissecting the pathogenesis of classical Hodgkin lymphoma (cHL), a common cancer in young adults, remains challenging because of the rarity of tumor cells in involved tissues (usually <5%). Here, we analyzed the coding genome of cHL by microdissecting tumor and normal cells from 34 patient biopsies for a total of ∼50 000 singly isolated lymphoma cells. We uncovered several recurrently mutated genes, namely, (32% of cases), (24%), (18%), and (16%), and document the functional role of mutant STAT6 in sustaining tumor cell viability. Mutations of genetically and functionally cooperated with disruption of , a JAK-STAT pathway inhibitor, to promote cHL growth. Overall, 87% of cases showed dysregulation of the JAK-STAT pathway by genetic alterations in multiple genes (also including , , , , and ), attesting to the pivotal role of this pathway in cHL pathogenesis and highlighting its potential as a new therapeutic target in this disease.
解析经典霍奇金淋巴瘤（cHL）的发病机制仍然具有挑战性，因为受累组织中的肿瘤细胞很少（通常<5%）。在这里，我们通过对 34 例患者活检中的肿瘤和正常细胞进行显微解剖，对 cHL 的编码基因组进行了分析，总共分析了约 50000 个单个分离的淋巴瘤细胞。我们发现了几个经常发生突变的基因，即 （32%的病例）、 （24%）、 （18%）和 （16%），并证明了突变 STAT6 在维持肿瘤细胞活力中的功能作用。突变的 基因在功能上与 JAK-STAT 通路抑制剂 的破坏相互配合，促进 cHL 的生长。总体而言，87%的病例表现出多个基因（还包括 、 、 、 和 ）的遗传改变导致 JAK-STAT 通路失调，这证明了该通路在 cHL 发病机制中的关键作用，并突出了其作为该疾病新的治疗靶点的潜力。
