Format

Send to

Choose Destination
Blood. 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.

Author information

1
Department of Lymphoid Cancer Research, British Columbia Cancer Agency, Vancouver, Canada.
2
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
3
Institute of Pathology, University of Würzburg, Würzburg, Germany.
4
Comprehensive Cancer Centre Mainfranken, Würzburg, Germany.
5
University Paris Descartes, Paris, France.
6
Département de Pathologie-Service d'Hématologie-Plateforme de Ressources Biologiques, Groupe Hospitalier Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France.
7
INSERM U955, Créteil, France.
8
Université Paris Est, Créteil, France.
9
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and.
10
Department of Pathology, University of Arizona, Tucson, AZ.

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.

PMID:
29467182
DOI:
10.1182/blood-2017-09-808907
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center