Abstract
Leukemias are frequently characterized by the expression of oncogenic fusion chimeras that normally arise due to chromosomal rearrangements. Intergenically spliced chimeric RNAs (ISC) are transcribed in the absence of structural genomic changes, and aberrant ISC expression is now recognized as a potential driver of cancer. To better understand these potential oncogenic drivers, high-throughput RNA sequencing was performed on T-acute lymphoblastic leukemia (T-ALL) patient specimens (n = 24), and candidate T-ALL-related ISCs were identified (n = 55; a median of 4/patient). In-depth characterization of the NFATC3-PLA2G15 chimera, which was variably expressed in primary T-ALL, was performed. Functional assessment revealed that the fusion had lower activity than wild-type NFATC3 in vitro, and T-ALLs with elevated NFATC3-PLA2G15 levels had reduced transcription of canonical NFAT pathway genes in vivo Strikingly, high expression of the NFATC3-PLA2G15 chimera correlated with aggressive disease biology in murine patient-derived T-ALL xenografts, and poor prognosis in human T-ALL patients. Mol Cancer Res; 16(3); 470-5. ©2018 AACR.
Highlights
Gene fusion is a frequent hallmark of leukemia and can arise due to a variety of structural chromosomal rearrangements, including translocation (e.g., BCR-ABL1), inversion (e.g., CBFbMYH11), and interstitial deletion (e.g., FIP1L1-PDGFRA; ref. 1)
We detected a high frequency of T-acute lymphoblastic leukemia (T-ALL)–associated Intergenically spliced chimeric RNAs (ISC) and notably found that expression of the NFATC3-PLA2G15 chimera correlated with aggressive disease biology
The analysis was performed using RNA sequencing (RNA-seq) data from 20 T-ALL samples, which were defined as being NFATC3-PLA2G15– high or low according to the results of NFATC3-PLA2G15 qRTPCR
Summary
Gene fusion is a frequent hallmark of leukemia and can arise due to a variety of structural chromosomal rearrangements, including translocation (e.g., BCR-ABL1), inversion (e.g., CBFbMYH11), and interstitial deletion (e.g., FIP1L1-PDGFRA; ref. 1). Gene fusion is a frequent hallmark of leukemia and can arise due to a variety of structural chromosomal rearrangements, including translocation (e.g., BCR-ABL1), inversion (e.g., CBFbMYH11), and interstitial deletion The advent of high-throughput RNA sequencing (RNA-seq) has provided novel insights into the transcriptional landscapes of normal and malignant cells. It is clear that expression of fusion mRNAs in the absence of structural rearrangements is more common than previously recognized. Expression of the resultant intergenically spliced chimeric mRNAs (ISC) is frequent in normal cells [5, 6]. Mounting evidence suggests that multiple cancers demonstrate aberrant ISC expression and that experimental inhibition of specific fusion transcripts can be toxic for malignant cells [7, 8]. We detected a high frequency of T-ALL–associated ISCs and notably found that expression of the NFATC3-PLA2G15 chimera correlated with aggressive disease biology
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