Credit: Rhoda Baer
Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.
Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.
And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.
“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.
To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.
As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.
Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.
In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.
The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.
Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.
When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.
The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.
