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

Abstract : 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.
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Jonathan Bond, Christine Tran Quang, Guillaume Hypolite, Mohamed Belhocine, Aurélie Bergon, et al.. Novel Intergenically Spliced Chimera, NFATC3-PLA2G15 , Is Associated with Aggressive T-ALL Biology and Outcome. Molecular Cancer Research, American Association for Cancer Research, 2018, ⟨10.1158/1541-7786.MCR-17-0442⟩. ⟨hal-01716815⟩

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