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

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, 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, and PTPN1), attesting to the pivotal role of this pathway in cHL pathogenesis and highlighting its potential as a new therapeutic target in this disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • DNA Mutational Analysis
  • Gene Expression Regulation, Neoplastic*
  • Hodgkin Disease / genetics*
  • Hodgkin Disease / metabolism
  • Hodgkin Disease / pathology
  • Humans
  • Janus Kinases / genetics*
  • Janus Kinases / metabolism
  • Mutation*
  • STAT Transcription Factors / genetics*
  • STAT Transcription Factors / metabolism
  • Signal Transduction


  • STAT Transcription Factors
  • Janus Kinases