Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia
| Autor: | Shunsuke Kimura, Lindsey Montefiori, Ilaria Iacobucci, Yaqi Zhao, Qingsong Gao, Elisabeth M. Paietta, Claudia Haferlach, A. Douglas Laird, Paul E. Mead, Zhaohui Gu, Wendy Stock, Mark Litzow, Jacob M. Rowe, Selina M. Luger, Stephen P. Hunger, Georgina L. Ryland, Breon Schmidt, Paul G. Ekert, Alicia Oshlack, Sean M. Grimmond, Jacqueline Rehn, James Breen, David Yeung, Deborah L. White, Ibrahim Aldoss, Elias J. Jabbour, Ching-Hon Pui, Manja Meggendorfer, Wencke Walter, Wolfgang Kern, Torsten Haferlach, Samuel Brady, Jinghui Zhang, Kathryn G. Roberts, Piers Blombery, Charles G. Mullighan |
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| Rok vydání: | 2022 |
| Předmět: |
Adult
Male Lymphoid Neoplasia Adolescent Immunology Genomics Cell Biology Hematology Middle Aged Precursor Cell Lymphoblastic Leukemia-Lymphoma Prognosis Biochemistry Chromatin Young Adult Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Humans CDX2 Transcription Factor Female Child Transcriptome Pol1 Transcription Initiation Complex Proteins Aged Transcription Factors |
| Zdroj: | Blood |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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