Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia

Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):3035-40. doi: 10.1073/pnas.1214326110. Epub 2013 Feb 4.

Abstract

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the Western hemisphere. Tumor-specific chromosomal translocations, characteristic findings in several human malignancies that directly lead to malignant transformation, have not been identified in CLL. Using paired-end transcriptome sequencing, we identified recurrent and reciprocal RNA chimeras involving yippee like 5 (YPEL5) and serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB) in CLL. Two of seven index cases (28%) harbored the reciprocal RNA chimeras in our initial screening. Using quantitative real-time PCR (q real-time PCR), YPEL5/PPP1CB and PPP1CB/YPEL5 fusion transcripts were detected in 97 of 103 CLL samples (95%) but not in paired normal samples, benign lymphocytes, or various unrelated cancers. Whole-genome sequencing and Southern blotting demonstrated no evidence for a genomic fusion between YPEL5 and PPP1CB. YPEL5/PPP1CB chimera, when introduced into mammalian cells, expressed a truncated PPP1CB protein that demonstrated diminished phosphatase activity. PPP1CB silencing resulted in enhanced proliferation and colony formation of MEC1 and JVM3 cells, implying a role in the pathogenesis of mature B-cell leukemia. These studies uncover a potential role for recurrent RNA chimeras involving phosphatases in the pathogenesis of a common form of leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Southern
  • Catalytic Domain
  • Cell Cycle Proteins / genetics*
  • Gene Fusion
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Protein Phosphatase 1 / genetics*
  • RNA, Neoplasm / genetics*
  • Real-Time Polymerase Chain Reaction

Substances

  • Cell Cycle Proteins
  • RNA, Neoplasm
  • YPEL5 protein, human
  • PPP1CB protein, human
  • Protein Phosphatase 1