UBC Theses and Dissertations
Identification and characterization of novel recurrent mutations in primary mediastinal large B cell lymphoma and Hodgkin lymphoma. Gunawardana, Jithendra
Classical Hodgkin lymphoma (HL) and primary mediastinal large B cell lymphoma (PMBCL) are related lymphomas sharing pathological, molecular and clinical characteristics. Here we discovered by next-generation sequencing recurrent somatic coding-sequence mutations in the protein tyrosine phosphatase PTPN1 and the cytokine receptor IL4R. Mutations in PTPN1 were found in 6 of 30 (20%) HL cases, in 6 of 9 (67%) HL–derived cell lines, in 17 of 77 (22%) PMBCL cases and in 1 of 3 (33%) PMBCL-derived cell lines, consisting of nonsense, missense and frameshift mutations. We demonstrate that PTPN1 mutations lead to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members. Moreover, silencing of PTPN1 by RNA interference in HL cell line KM-H2 resulted in hyperphosphorylation and overexpression of the downstream oncogenes BCL6 and MYC. Mutations in IL4R were found in 18 of 65 (28%) PMBCL cases confirming a ‘hotspot’ missense mutation I242N in exon 8 in 11 of 18 (61%) mutated cases. Ectopic expression of the mutant I242N in HEK 293 cells showed increased activated STAT6-dependent SEAP reporter gene expression without interleukin-4 stimulation. Introduction of the mutant into Hodgkin lymphoma cell line DEV showed cytokine-independent hyperphosphorylation of JAK-STAT pathway members and upregulation of the T cell regulatory chemokine TARC (CCL17) and the B cell activation marker CD23. Our data suggest loss-of-function PTPN1 and gain-of-function IL4R mutations leading to oncogenic JAK-STAT activation as new driver alterations in lymphomagenesis with implications for future treatment strategies.
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