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. 2018 May 3;131(18):2036-2046.
doi: 10.1182/blood-2017-09-808907. Epub 2018 Feb 21.

Somatic IL4R mutations in primary mediastinal large B-cell lymphoma lead to constitutive JAK-STAT signaling activation

Elena Viganò  1   2 , Jay Gunawardana  1   2 , Anja Mottok  1   2   3   4 , Tessa Van Tol  1 , Katina Mak  1 , Fong Chun Chan  1   2 , Lauren Chong  1 , Elizabeth Chavez  1 , Bruce Woolcock  1 , Katsuyoshi Takata  1 , David Twa  1   2 , Hennady P Shulha  1 , Adèle Telenius  1 , Olga Kutovaya  1   2 , Stacy S Hung  1 , Shannon Healy  1   2 , Susana Ben-Neriah  1 , Karen Leroy  5 , Philippe Gaulard  6   7   8 , Arjan Diepstra  9 , Robert Kridel  1   2 , Kerry J Savage  1 , Lisa Rimsza  10 , Randy Gascoyne  1   2 , Christian Steidl  1   2
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Somatic IL4R mutations in primary mediastinal large B-cell lymphoma lead to constitutive JAK-STAT signaling activation

Elena Viganò et al. Blood. .
Free article

Abstract

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 somatic IL4R mutations in 15 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 advantage in vivo. The pattern of concurrent mutations within the JAK-STAT signaling pathway suggests additive/synergistic effects of these gene mutations contributing to lymphomagenesis. Our data establish IL4R mutations as novel driver alterations and provide a strong preclinical rationale for therapeutic targeting of JAK-STAT signaling in PMBCL.

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