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

1 Scopus citations

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 (US)
Pages (from-to)6039-6053
Number of pages15
JournalClinical Cancer Research
Volume27
Issue number21
DOIs
StatePublished - Nov 15 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Genome-wide miRNA expression profiling of molecular subgroups of peripheral T-cell lymphoma'. Together they form a unique fingerprint.

Cite this