S102: Comprehensive Genome Characterization Reveals New Subtypes and Mechanisms of Oncogene Deregulation in Childhood T-all
Year: 2022
Type: article
Abstract: Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy including leukemias of early T cell precursor acute lymphoblastic leukemia (ETP-ALL) and transformed thymocytes. Prior genomic studies of T-ALL had limited cohort size, excluded refractory disease and focused on alterations in coding parts of the genome. Aims: Investigate the genomic basis of T-ALL by identifying both coding and non-coding alterations and defining T-ALL subtypes. Methods: We performed whole-genome sequencing (WGS), whole-exome sequencing (WES), RNA-sequencing of 1,313 cases enrolled on the Children’s Oncology Group AALL0434 trial. Results: Uniform Manifold Approximation and Projection (UMAP) and gene expression clustering analyses of RNA-seq data identified 16 subtypes, of which 4 have not been reported previously. Furthermore, we could divide existing subtypes into smaller subgroups with common subtype-defining alterations, such as structural variation (SV) and copy number variation (CNV). TLX1 activation was linked with TLX1-TCR SVs and deletions in the TLX1 chromosomal domain, whereas TLX3 deregulation was associated with TLX3-BCL11B enhancer hijacking, but also through TLX3-TCR, TLX3-CDK6 rearrangements. We discovered two separate NKX2-1 deregulated groups, one characterized by TCR rearrangements and RPL10 mutations and the other by NKX2-1 CNVs, chromosome 14 chromothripsis, or MYB-TCR rearrangements. We also observed a distinct group of 9 cases aged 1-2 years, with recurrent STAG2-LMO2 rearrangements and a patient with inactivating STAG2 mutation and CELF1 enhancer hijacking by LMO2. Moreover, we found a group of 22 cases that were highly enriched for ETP-ALL with the following hallmark lesions: BCL11B enhancer amplification, BCL11B locus SVs involving enhancer hijacking of ARID1B, CCDC26, and novel CD34+ enhancer hijacking of lincRNA locus in chromosome 6. Gene expression-based clustering was unable to stratify patients based on TAL1, TAL2, LMO1, LMO2, LYL1 expression, and their respective activation mechanisms. However, WGS enabled further characterization of these patients, by identifying several types of activation mechanisms and co-occurring alterations for each oncogene. We identified canonical events, such as TAL1-STIL fusions, TCR rearrangements, and activation by TAL1/LMO1/LMO2 regulatory region indels, but also novel events, such as CD34 specific enhancer duplications downstream of TAL1 and BCL11B enhancer hijacking by LMO2. We also observed two smaller clusters with TAL1/LMO2 activation, where one with 39 cases was associated with TAL1/LMO2 activation and RPL10 mutations and the other with 8 cases had refractory disease (Day 29 MRD >5%). HOXA gene expression-associated subtypes were defined by fusions involving KMT2A or MLLT10 and PICALM/DDX3X or HOXA9-TCR SVs. Furthermore, our analysis revealed segregation of patients by HOXA13 or ZFP36L2 rearrangements and NUP98/NUP214 fusions. Interestingly, HOXA locus breakpoints involving HOXA13 and HOXA9 were in different chromatin compartments and were associated with mutually exclusive activation of either HOXA13 or other HOXA genes. Interestingly, HOXA13-deregulation was associated with ETP-ALL and frequent BCL11B enhancer hijacking, whereas HOXA9 breakpoints typically involved TCRg and were non-ETP. Image:Summary/Conclusion: Large-scale analysis of all children enrolled on the AALL0434 study has identified new subtype-defining lesions in T-ALL, including candidate novel enhancer hijacking events and enhancer duplications that are likely to result in oncogene deregulation in T-ALL.
Source: HemaSphere
Authors: P. Pölönen, A. Elsayed, L. Montefiori, S. Kimura, J. Myers, D. Hedges, J. Xu, Y. Hui, Z. Cheng, Y. Fan, Y. Chang, R. Shraim, M. Devidas, S. Winter, K. Dunsmore, J. J. Yang, T. L. Vincent, K. Tan, C. Chen, H. Newman, M. Loh, E. Raetz, S. P. Hunger, E. Rampersaud, T.-C. Chang, G. Wu, S. Pounds, C. G. Mullighan, D. T. Teachey
Institutions: St. Jude Children's Research Hospital, University of Pennsylvania, Children's Hospital of Philadelphia, Children's Minnesota, University of Virginia Children's Hospital, University of California, San Francisco, UCSF Benioff Children's Hospital, UCSF Helen Diller Family Comprehensive Cancer Center, NYU Langone Health, NYU Langone’s Laura and Isaac Perlmutter Cancer Center
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,480
OpenAlex ID: W4283326708