Citations 1
Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma
Lone, Waseem , Bouska, Alyssa , Sharma, Sunandini , Amador, Catalina, Herek, Tyler A. , Heavican, Tayla B., Yu, Jiayu , Lim, Soon Thye , Ong, Choon Kiat , Slack, Graham W. , Savage, Kerry J. , Rosenwald, Andreas , Ott, German , Cook, James R. , Greiner, Timothy C. , Weisenburger, Dennis D. , Motta, Giovanna , Chan, Wing C. , Iqbal, Javeed , Saumyaranjan, Mallick , Ong, Choon Kiat , Feldman, Andrew L , Weisenburger, Dennis D , Melle, Federica , Savage, Kerry J , Bouska, Alyssa , Iqbal, Javeed , Lone, Waseem G , Feldman, Andrew L. , Rimsza, Lisa M. , McKeithan, Timothy W. , Pileri, Stefano , Vose, Julie M.
Clinical Cancer Research | August 23, 2021 | Volume: 27 | Issue: 21 | Pages: 6039-6053
Abstract 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 of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling 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 and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were 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 pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.