Abstract LB-345: Unique molecular identifiers of indolent versus aggressive phenotyping in non-Hodgkin lymphoma: Spotlight on SMZL
Authors: Robinson Jacob E. , Cutucache Christine E. 
Published: August 2018

Splenic marginal zone lymphoma (SMZL) is an indolent, non-Hodgkin's lymphoma that lacks clear genotypic classification. Approximately 30% of all SMZL cases will become aggressive or undergo transformation to a more lethal lymphoma. Hence, the main purpose of this study was to broadly characterize the molecular profiles of SMZL cases, compared with healthy B-cell controls and other B-cell lymphomas (BCLs), in an effort to delineate the variable malignant presentations. We aimed to identify a unique indolent and aggressive gene expression signature among SMZL cases in order to potentially provide prognostic value.

We conducted a meta-analysis of previously published gene expression data to identify genes most dysregulated in SMZL. We aimed to delineate the “indolent phenotype” and the “aggressive phenotype” by comparing SMZL to more aggressive BCLs as well as healthy B-cell controls, in order to extract a prognostic gene expression profile specific to SMZL. Markers potentially demonstrating an “aggressive” signature were those significantly up or down regulated in SMZL samples when compared to BCLs and healthy controls. The most upregulated genes in SMZL included PPBP, CXCL6, HBB, KAZN, NTN4, SLC40A1, MAFB, ATP1B1, and C1QB, while the most downregulated genes were RASSF6, RGS13, ELL3, LHFPL2, and SYB. Pathways impacted include immune defense (inclusive of leukocyte chemotaxis), motility (inclusive of lamellipodium assembly), cell proliferation, and many other mechanisms.

Contrarily, 19 key markers of potential oncogenic indolency (i.e. down regulated compared with other, aggressive B-cell lymphomas, but upregulated compared with healthy B-cells) were also identified: ABI3BP, GPNMB, LUM, CCL19, ADAMDEC1, GJA1, MGP, SERPINF1, COL6A3, C3, RARRES1, FN1, CCL18, PRRX1, RGS5, CHI3L1, COL5A2, LOXL1, and ANKRD29. Additionally, a transcription factor, ZC3H7B, known to play a role in BCL6 repression as a result of a fusion with BCOR, is uniquely down regulated in SMZL compared with normal B controls while being up regulated when compared to similar BCLs. This exclusive expression of ZC3H7B represents a unique marker for SMZL identification compared to other BCLs. The aforementioned gene expression profile provides SMZL identification potential, and more importantly, these unique gene signatures potentially identify markers of indolent progression due to their differential expression from more aggressive B-cell lymphoma counterparts. Further investigations into the translatability of these gene expressions and their resultant impacted pathways will be evaluated for diagnostic and prognostic significance using immunohistochemistry, and hypothesized targets will be evaluated in vitro. Ultimately, we expect that the unique gene expression profile identified in this study will provide translatable results to assist with patient staging in SMZL.

Citation Format: Jacob E. Robinson, Christine E. Cutucache. Unique molecular identifiers of indolent versus aggressive phenotyping in non-Hodgkin lymphoma: Spotlight on SMZL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-345.