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

Waseem Lone, Alyssa Bouska, Sunandini Sharma, Catalina Amador, Mallick Saumyaranjan, Tyler A Herek, Tayla B Heavican, Jiayu Yu, Soon Thye Lim, Choon Kiat Ong, Graham W Slack, Kerry J Savage, Andreas Rosenwald, German Ott, James R Cook, Andrew L Feldman, Lisa M Rimsza, Timothy W McKeithan, Timothy C Greiner, Dennis D WeisenburgerFederica Melle, Giovanna Motta, Stefano Pileri, Julie M Vose, Wing C Chan, Javeed Iqbal

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)6039-6053
Number of pages15
JournalClin. Cancer Res.
Volume27
Issue number21
DOIs
Publication statusPublished - Nov 1 2021

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