Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma

Abstract

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, <i>STAT6</i> (32% of cases), <i>GNA13</i> (24%), <i>XPO1</i> (18%), and <i>ITPKB</i> (16%), and document the functional role of mutant STAT6 in sustaining tumor cell viability. Mutations of <i>STAT6</i> genetically and functionally cooperated with disruption of <i>SOCS1</i>, 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 <i>STAT3</i>, <i>STAT5B</i>, <i>JAK1</i>, <i>JAK2</i>, and <i>PTPN1</i>), attesting to the pivotal role of this pathway in cHL pathogenesis and highlighting its potential as a new therapeutic target in this disease.