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https://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.S. Wadham, C. Shanmuganathan, N. Scott, H.S. Dinger, M.E. Hughes, T.P. Schreiber, A.W. Branford, S. |
Citation: | Leukemia, 2020; 34(8):2051-2063 |
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. |
Keywords: | Humans Blast Crisis DNA Nucleotidylexotransferase DNA-Binding Proteins Homeodomain Proteins Nuclear Proteins Computational Biology Gene Deletion Recombination, Genetic Leukemia, Myelogenous, Chronic, BCR-ABL Positive |
Description: | Published: 19 February 2020 |
Rights: | © The Author(s), under exclusive licence to Springer Nature Limited 2020 |
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 |
Published version: | http://dx.doi.org/10.1038/s41375-020-0751-y |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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