Abstract
PTPN1 mutations recur in primary mediastinal B-cell lymphoma (PMBCL) and classical Hodgkin lymphoma.
Major finding: PTPN1 mutations recur in primary mediastinal B-cell lymphoma (PMBCL) and classical Hodgkin lymphoma.
Concept: PTPN1 mutations reduce phosphatase activity and increase phosphorylation of JAK–STAT pathway components.
Impact: Inactivation of PTPN1 may be a driving event in PMBCL and classical Hodgkin lymphoma.
Primary mediastinal B-cell lymphoma (PMBCL) is an aggressive B-cell non-Hodgkin lymphoma subtype that shares clinical, pathologic, and molecular features with classical Hodgkin lymphoma. To gain insight into the etiology of PMBCL, Gunawardana and colleagues performed whole-genome and whole-transcriptome sequencing of 2 PMBCL samples and whole-transcriptome sequencing of 5 additional PMBCLs and identified mutations in protein tyrosine phosphatase, nonreceptor type 1 (PTPN1, also known as PTP1B) in 3 PMBCLs. A screen of a larger cohort of 70 PMBCL samples and 30 cases of classical Hodgkin lymphoma revealed that PTPN1 was mutated in 17 of 77 (22%) PMBCLs and 6 of 30 (20%) classical Hodgkin lymphomas. The mutations were largely missense, nonsense, or frameshift mutations or single amino-acid deletions and were associated with decreased PTPN1 protein expression and reduced PTPN1 phosphatase activity, suggesting that PMBCL- and classical Hodgkin lymphoma-associated PTPN1 mutations lead to loss of PTPN1 function. To determine the functional consequences of PTPN1 inactivation, the authors knocked down PTPN1 in a Hodgkin lymphoma cell line and observed hyperphosphorylation of multiple components of the JAK–STAT pathway, including STAT3, STAT5, STAT6, JAK1, and JAK2. Analysis of differentially expressed genes in PTPN1-silenced cells confirmed an enrichment of STAT3 target genes and genes involved in JAK–STAT signaling. Together, these findings implicate PTPN1 as a tumor suppressor gene in PMBCL and classical Hodgkin lymphoma and suggest that loss of PTPN1 phosphatase activity may promote the development of these cancers by leading to aberrant activation of the JAK–STAT pathway.