Cell Behavior

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

Published on - Molecular Cancer Research

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

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.