Novel Intergenically Spliced Chimera, NFATC3-PLA2G15 , Is Associated with Aggressive T-ALL Biology and Outcome


  • Bond Jonathan
  • Tran Quang Christine
  • Hypolite Guillaume
  • Belhocine Mohamed
  • Bergon Aurélie
  • Cordonnier Gaëlle
  • Ghysdael Jacques
  • Macintyre Elizabeth
  • Boissel Nicolas
  • Spicuglia Salvatore
  • Asnafi Vahid


  • T-acute lymphoblastic leukemia
  • Oncogene
  • Intergenically-spliced chimera
  • RNA-sequencing
  • Nuclear Factor of Activated T-cells

document type



Leukemias are frequently characterized by the expression of oncogenic fusion chimeras that normally a rise due to chromosomal rearrangements. Cis-splicing of adjacent genes (cis-SAGe) results in transcription of intergenically-spliced chimeric RNAs (ISCs) in the absence of structural genomic changes, and aberrant ISC expression is now recognized as a potential cancer driver. We performed high-throughput RNA-sequencing of human T-acute lymphoblastic leukemia (T-ALL) samples, and used targeted analysis pipelines to detect fusion chimeras. We identified 55 candidate T-ALL-related ISCs, with a median of 4 per patient. We performed additional in-depth characterization of the NFATC3-PLA2G15 chimera, which was expressed at variable levels in primary T-ALL cases. Experimental analysis revealed that the fusion had lower activity than wild-type NFATC3 in vitro, and that T-ALL blasts with elevated NFATC3-PLA2G15 levels had reduced transcription of canonical NFAT pathway genes in vivo. Strikingly, we found that high expression of the NFATC3-PLA2G15 chimera in leukemic blasts correlated with aggressive disease biology in murine patient-derived T-ALL xenografts,and poor prognosis in human T-ALLpatients treated as part of the Francophone multinational GRAALL-2003 and -2005 studies. Our results suggest that ISCs are common in T-ALL, and that expression of specific ISCs may correlate with patient outcome.

more information