SOCS1 Mutation Subtypes Predict Divergent Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) Patients

Abstract

Suppressor of cytokine signaling 1 (SOCS1) is frequently mutated in primary mediastinal and diffuse large B-cell lymphomas (DLBCL). Currently, the prognostic relevance of these mutations in DLBCL is unknown. To evaluate the value of the SOCS1 mutation status as a prognostic biomarker in DLBCL patients, we performed full-length SOCS1 sequencing in tumors of 154 comprehensively characterized DLBCL patients. We identified 90 SOCS1 mutations in 16% of lymphomas. With respect to molecular consequences of mutations, we defined two distinct subtypes: those with truncating (major) and those with non-truncating mutations (minor), respectively. The SOCS1 mutated subgroup or the minor/major subtypes cannot be predicted on clinical grounds; however, assignment of four established gene-expression profile-based classifiers revealed significant associations of SOCS1 major cases with germinal center and specific pathway activation pattern signatures. Above all, SOCS1 major cases have an excellent overall survival, even better than the GCB-like subgroup. SOCS1 minor cases had a dismal survival, even worse than the ABC gene signature group. The SOCS1 mutation subsets retained prognostic significance in uni- and multivariate analyses. Together our data indicate that assessment of the SOCS1 mutation status is a single gene prognostic biomarker in DLBCL.

Genetic Landscapes of Relapsed and Refractory Diffuse Large B-Cell Lymphomas

“…Supporting this, STAT6-D419-mutated PMBCL cell lines depend on STAT6 signaling for their survival and are more sensitive to JAK2 inhibitors compared with STAT6 wildtype PMBCL cell lines (23,47). Other mechanisms of increased JAK/STAT signaling have been reported in diagnostic DLBCL samples, such as mutations in SOCS1 and STAT3 (48,49). However, these occurred in less than 5% of our cohort, suggesting that JAK/STAT signaling at relapse is predominantly driven by STAT6 mutations and represents a new therapeutic target for patients with TLy and rr-GCB-DLBCL (48,49).…”

“…Other mechanisms of increased JAK/STAT signaling have been reported in diagnostic DLBCL samples, such as mutations in SOCS1 and STAT3 (48,49). However, these occurred in less than 5% of our cohort, suggesting that JAK/STAT signaling at relapse is predominantly driven by STAT6 mutations and represents a new therapeutic target for patients with TLy and rr-GCB-DLBCL (48,49). Given that JAK2 inhibitors are routinely used to treat JAK2-mutated myeloproliferative disorders, and they are active in STAT6-mutant PMBCL cell lines, they could be readily tested in the setting of STAT6-mutated rrDLBCL in future clinical trials.…”

NF-κB Transcriptional Activity Is Modulated by FK506-binding Proteins FKBP51 and FKBP52

“…up-regulated (65)(66)(67), whereas the E3-ubiquitin-ligase of RelA, SOCS1, is down-regulated (68 -70) or mutated (71), all of which may contribute to the constitutive activation of NF-B in those cancers. A similar mechanism can be proposed here for the expression balance of FKBP51 and FKBP52, in particular for the latter immunophilin, which shows an important stimulatory action dependent on its PPIase activity.…”

SOCS1 gene mutations in patients with diffuse large B-cell lymphoma

“…мутации в гене SOCS1 [45]. Все случаи охарактеризованы не толь-ко клинически и в зависимости от терапии, но и с применением 6 различных прогностических моделей, общепринятых в настоя-щее время (иммуногистохимическая, цитогенетическая и 4 моле-кулярные, выделяющие различные по биологии типы ДВККЛ [46][47][48][49]).…”

“…Нуклеотиды G/C (n=64) вовлекались чаще, чем нуклеотиды A/T (n=12) -26 про-тив 5 в соматических гипермутациях. Частота, расположение и трансляционная последовательность мутаций SOCS1 по полу-ченным данным подтверждали гипотезу, что они вызваны абер-рантной соматической гипермутацией [45].…”