Deciphering genes associated with diffuse large B-cell lymphoma with lymphomatous effusions: A mutational accumulation scoring approach

Abstract

Introduction Earlier studies have shown that lymphomatous effusions in patients with diffuse large B-cell lymphoma (DLBCL) are associated with a very poor prognosis, even worse than for non-effusion-associated patients with stage IV disease. We hypothesized that certain genetic abnormalities were associated with lymphomatous effusions, which would help to identify related pathways, oncogenic mechanisms, and therapeutic targets. Methods We compared whole-exome sequencing on DLBCL samples involving solid organs (n = 22) and involving effusions (n = 9). We designed a mutational accumulation-based approach to score each gene and used mutation interpreters to identify candidate pathogenic genes associated with lymphomatous effusions. Moreover, we performed gene-set enrichment analysis from a microarray comparison of effusion-associated versus non-effusion-associated DLBCL cases to extract the related pathways. Results We found that genes involved in identified pathways or with high accumulation scores in the effusion-based DLBCL cases were associated with migration/invasion. We validated expression of 8 selected genes in DLBCL cell lines and clinical samples: MUC4, SLC35G6, TP53BP2, ARAP3, IL13RA1, PDIA4, HDAC1 and MDM2, and validated expression of 3 proteins (MUC4, HDAC1 and MDM2) in an independent cohort of DLBCL cases with (n = 31) and without (n = 20) lymphomatous effusions. We found that overexpression of HDAC1 and MDM2 correlated with the presence of lymphomatous effusions, and HDAC1 overexpression was associated with the poorest prognosis. Conclusion Our findings suggest that DLBCL associated with lymphomatous effusions may be associated mechanistically with TP53-MDM2 pathway and HDAC-related chromatin remodeling mechanisms.

Targeting HDACs for diffuse large B-cell lymphoma therapy

“…Among the HDAC family members, HDAC1 has been well characterized and may indicate a poor prognosis in DLBCL cases 31 . Its overexpression has been correlated with poor prognosis in diffuse large B-cell lymphoma 32 . Chidamide, as a selective inhibitor of HDAC1 and HDAC2, may be a treatment option for DLBCL patients with HDAC1 and HDAC2 overexpression.…”

High expression of TMEM244 is associated with poor overall survival of patients with T-cell lymphoma

“…However, current risk stratification based on the international prognostic index (including age, Ann Arbor stage, performance status, serum lactate dehydrogenase level, and extranodal involvement) cannot accurately predict the prognosis of all TCL patients [6,7]. However, genetics in TCL are lacking for supplementing risk stratification to relatively accurately predict the prognosis of TCL patients [6,[8][9][10]. In our previous publications, we found that transmembrane protein 244 gene (TMEM244) is ectopically expressed in Sézary syndrome (SS), driven by hypomethylation of the promoter region [11,12].…”

Single‐cell profiling guided combination therapy of c‐Fos and histone deacetylase inhibitors in diffuse large B‐cell lymphoma

“… 2 This also applies to DLBCL cells in which an overexpression of HDAC1 ties in with worse prognosis. 3 To date, five HDACs inhibitors (HDACi) have been approved by the Food and Drug Administration (FDA) USA and the FDA China for use in patients with cutaneous T cell lymphoma and multiple myeloma. These are active against all four zinc‐dependent HDACs (classes I, II and IV; pan‐HDACi; Figure 1A ) or specifically target HDAC subtypes 2 , 4 (Figure 1B ).…”

“…A frequent dysregulation of HDACs in cancer cells has spurred an intense search on small molecules that inhibit them 2 . This also applies to DLBCL cells in which an overexpression of HDAC1 ties in with worse prognosis 3 . To date, five HDACs inhibitors (HDACi) have been approved by the Food and Drug Administration (FDA) USA and the FDA China for use in patients with cutaneous T cell lymphoma and multiple myeloma.…”