Somatic IL4R Mutations in Primary Mediastinal Large B-cell lymphoma lead to constitutive JAK-STAT signaling activation

Primary mediastinal large B cell lymphoma (PMBCL) is a distinct subtype of diffuse large B cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somaticIL4Rmutations in 15 out of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8 leading to an I242N amino acid change in the transmembrane domain. Functional analyses establish this mutation as gain-of-function leading to constitutive activation of the JAK-STAT pathway and upregulation of downstream cytokine expression profiles and B cell specific antigens. Moreover, expression of I242N mutant IL4R in a mouse xenotransplantation model conferred growth advantagein vivoThe pattern of concurrent mutations within the JAK-STAT signaling pathway suggests additive/synergistic effects of these gene mutations contributing to lymphomagenesis. Our data establishIL4Rmutations as novel driver alterations and provide a strong preclinical rationale for therapeutic targeting of JAK-STAT signaling in PMBCL