Systematic fusion transcript discovery in mantle cell lymphoma using long-read sequencing

Area of Science:

• Genomics
• Transcriptomics
• Cancer Biology

Background:

• Fusion transcripts, arising from distinct genes, are crucial for identifying cancer biomarkers and therapeutic targets.
• Detecting all fusion transcripts at the RNA level is vital for cancer research.

Purpose of the Study:

• To identify and characterize fusion transcripts in Mantle Cell Lymphoma (MCL) using long-read RNA sequencing.
• To investigate novel fusion transcripts, including those involving long non-coding RNAs.

Main Methods:

• Employed Iso Sequencing (third-generation long-read RNA sequencing) on MCL cell lines.
• Validated identified fusion transcripts using orthogonal techniques.
• Investigated the effect of CPSF73/CPSF3 inhibition on a specific fusion transcript.

Main Results:

• Revealed extensive transcript diversity and numerous novel transcripts in MCL.
• Identified several novel fusion transcripts, some of which were among the longest in the MCL transcriptome.
• Validated known (CTBS::GNG5) and novel fusion transcripts (RBM15::LAMTOR5:AS), including one involving a long non-coding RNA.
• Observed increased expression of RBM15::LAMTOR5:AS upon treatment with JT-607, a CPSF73/CPSF3 inhibitor.

Conclusions:

• The study identified a novel fusion transcript (RBM15::LAMTOR5:AS) and numerous other fusion transcripts in MCL.
• These findings underscore the importance of unbiased approaches for comprehensive fusion transcript identification.
• The discovered fusion transcripts contribute to understanding transcriptome complexity in cancer and normal biology.