Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma

Purpose: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4(+) Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis. Experimental Design: We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4(+) T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments. Results: Effector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration ofmiRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERKsignaling in Th1-polarized cells, and AKT-mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA-mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid andWnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma(AITL), while ERK, MAPK, andcell cyclewere identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. In silico and experimental validation suggest two targets (miR-126 -> SIPR2 and miR-145 -> ROCK1) resulting in reduced RhoA-GTPase activity and T-B-cell interaction. Conclusions: Unique miRNAs and deregulated oncogenic path-ways are associated with PTCL subtypes. Upregulated miRNA-126-3p andmiR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.

Automated summary

This study revealed differences in miRNA expression and signaling pathways among different subtypes of T-cell lymphoma, identifying certain miRNAs and possible regulatory mechanisms associated with disease occurrence and progression.