Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/123607
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Type: Journal article
Title: Aberrant RAG-mediated recombination contributes to multiple structural rearrangements in lymphoid blast crisis of chronic myeloid leukemia
Author: Thomson, D.W.
Shahrin, N.H.
Wang, P.P.
Wadham, C.
Shanmuganathan, N.
Scott, H.S.
Dinger, M.E.
Hughes, T.P.
Schreiber, A.W.
Branford, S.
Citation: Leukemia, 2020; OnlinePubl(8)
Publisher: Springer Nature
Issue Date: 2020
ISSN: 0887-6924
1476-5551
Statement of
Responsibility: 
Daniel W. Thomson, Nur Hezrin Shahrin, Paul P. S. Wang, Carol Wadham, Naranie Shanmuganathan, Hamish S. Scott, Marcel E. Dinger, Timothy P. Hughes, Andreas W. Schreiber, Susan Branford
Abstract: Blast crisis of chronic myeloid leukemia is associated with poor survival and the accumulation of genomic lesions. Using whole-exome and/or RNA sequencing of patients at chronic phase (CP, n = 49), myeloid blast crisis (MBC, n = 19), and lymphoid blast crisis (LBC, n = 20), we found 25 focal gene deletions and 14 fusions in 24 patients in BC. Deletions predominated in LBC (83% of structural variants). Transcriptional analysis identified the upregulation of genes involved in V(D)J recombination, including RAG1/2 and DNTT in LBC. RAG recombination is a reported mediator of IKZF1 deletion. We investigated the extent of RAG-mediated genomic lesions in BC. Molecular hallmarks of RAG activity; DNTT-mediated nucleotide insertions and a RAG-binding motif at structural variants were exclusively found in patients with high RAG expression. Structural variants in 65% of patients in LBC displayed these hallmarks compared with only 5% in MBC. RAG-mediated events included focal deletion and novel fusion of genes associated with hematologic cancer: IKZF1, RUNX1, CDKN2A/B, and RB1. Importantly, 8/8 patients with elevated DNTT at CP diagnosis progressed to LBC by 12 months, potentially enabling early prediction of LBC. This work confirms the central mutagenic role of RAG in LBC and describes potential clinical utility in CML management.
Description: Published: 19 February 2020
Rights: © The Author(s), under exclusive licence to Springer Nature Limited 2020
RMID: 1000014727
DOI: 10.1038/s41375-020-0751-y
Grant ID: http://purl.org/au-research/grants/nhmrc/1135949
http://purl.org/au-research/grants/nhmrc/1027531
http://purl.org/au-research/grants/nhmrc/1104425
http://purl.org/au-research/grants/nhmrc/1117718
Appears in Collections:Medicine publications

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