{"doi":"10.1182/blood.2022015444","title":"Enhancer retargeting of <i>CDX2</i> and <i>UBTF::ATXN7L3</i> define a subtype of high-risk B-progenitor acute lymphoblastic leukemia","abstract":"Transcriptome sequencing has identified multiple subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL) of prognostic significance, but a minority of cases lack a known genetic driver. Here, we used integrated whole-genome (WGS) and -transcriptome sequencing (RNA-seq), enhancer mapping, and chromatin topology analysis to identify previously unrecognized genomic drivers in B-ALL. Newly diagnosed (n = 3221) and relapsed (n = 177) B-ALL cases with tumor RNA-seq were studied. WGS was performed to detect mutations, structural variants, and copy number alterations. Integrated analysis of histone 3 lysine 27 acetylation and chromatin looping was performed using HiChIP. We identified a subset of 17 newly diagnosed and 5 relapsed B-ALL cases with a distinct gene expression profile and 2 universal and unique genomic alterations resulting from aberrant recombination-activating gene activation: a focal deletion downstream of PAN3 at 13q12.2 resulting in CDX2 deregulation by the PAN3 enhancer and a focal deletion of exons 18-21 of UBTF at 17q21.31 resulting in a chimeric fusion, UBTF::ATXN7L3. A subset of cases also had rearrangement and increased expression of the PAX5 gene, which is otherwise uncommon in B-ALL. Patients were more commonly female and young adult with median age 35 (range,12-70 years). The immunophenotype was characterized by CD10 negativity and immunoglobulin M positivity. Among 16 patients with known clinical response, 9 (56.3%) had high-risk features including relapse (n = 4) or minimal residual disease >1% at the end of remission induction (n = 5). CDX2-deregulated, UBTF::ATXN7L3 rearranged (CDX2/UBTF) B-ALL is a high-risk subtype of leukemia in young adults for which novel therapeutic approaches are required.","journal":"Blood","year":2022,"id":239007,"datarank":0.5955437870328184,"base_score":3.970291913552122,"endowment":3.970291913552122,"self_citation_contribution":0.5955437870328184,"citation_network_contribution":0.0,"self_endowment_contribution":0.5955437870328184,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":52,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":572761,"name":"Lindsey E. 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Mead","orcid":null,"position":8,"is_corresponding":false},{"id":253485,"name":"Zhaohui Gu","orcid":"0000-0003-1581-1327","position":9,"is_corresponding":false},{"id":230930,"name":"Wendy Stock","orcid":"0000-0002-8349-9200","position":10,"is_corresponding":false},{"id":284142,"name":"Mark R. Litzow","orcid":"0000-0002-9816-6302","position":11,"is_corresponding":false},{"id":721713,"name":"Jacob M. Rowe","orcid":"0000-0002-2016-2918","position":12,"is_corresponding":false},{"id":284260,"name":"Selina M. Luger","orcid":"0000-0003-3364-4366","position":13,"is_corresponding":false},{"id":301503,"name":"Stephen P. Hunger","orcid":"0000-0002-5492-3957","position":14,"is_corresponding":false},{"id":864200,"name":"Georgina L. Ryland","orcid":"0000-0002-4990-0961","position":15,"is_corresponding":false},{"id":864201,"name":"Breon Schmidt","orcid":"0000-0003-0341-3647","position":16,"is_corresponding":false},{"id":246735,"name":"Paul G. 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Brady","orcid":"0000-0001-5518-7800","position":31,"is_corresponding":false},{"id":1812,"name":"Jinghui Zhang","orcid":"0000-0003-3350-9682","position":32,"is_corresponding":false},{"id":247439,"name":"Kathryn G. Roberts","orcid":"0000-0001-7626-4043","position":33,"is_corresponding":false},{"id":109594,"name":"Piers Blombery","orcid":"0000-0002-9902-0022","position":34,"is_corresponding":false},{"id":247450,"name":"Charles G. 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