PERVASIVE MUTATIONS OF JAK-STAT PATHWAY GENES IN CLASSICAL HODGKIN LYMPHOMA

Dissecting the pathogenesis of classical Hodgkin lymphoma (cHL), a common cancer in young adults, remains challenging due to 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 STAT6 (32% of cases), GNA13 (24%), XPO1 (18%) and ITPKB (16%), and document the functional role of mutant STAT6 in sustaining tumor cell viability. Mutations of STAT6 genetically and functionally cooperated with disruption of SOCS1, 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 STAT3, STAT5B, JAK1, JAK2, PTPN1), attesting to the pivotal role of this pathway in cHL pathogenesis, and highlighting its potential as new therapeutic target in this disease.