@article{a2a5c32416b54aaba38705adca7f25c7,
title = "Enhancer retargeting of CDX2 and UBTF::ATXN7L3 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.",
author = "Shunsuke Kimura and Lindsey Montefiori and Ilaria Iacobucci and Yaqi Zhao and Qingsong Gao and Paietta, {Elisabeth M.} and Claudia Haferlach and Laird, {A. Douglas} and Mead, {Paul E.} and Zhaohui Gu and Wendy Stock and Mark Litzow and Rowe, {Jacob M.} and Luger, {Selina M.} and Hunger, {Stephen P.} and Ryland, {Georgina L.} and Breon Schmidt and Ekert, {Paul G.} and Alicia Oshlack and Grimmond, {Sean M.} and Jacqueline Rehn and James Breen and David Yeung and White, {Deborah L.} and Ibrahim Aldoss and Jabbour, {Elias J.} and Pui, {Ching Hon} and Manja Meggendorfer and Wencke Walter and Wolfgang Kern and Torsten Haferlach and Samuel Brady and Jinghui Zhang and Roberts, {Kathryn G.} and Piers Blombery and Mullighan, {Charles G.}",
note = "Funding Information: The authors are supported by the American and Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital; the St. Jude Children's Research Hospital Chromatin Collaborative (C.G.M.); National Institutes of Health National Cancer Institute (NCI) grants P30 CA021765, R35 CA197695 (C.G.M.), U10 CA180820 (ECOG-ACRIN), UG1 CA232760 (M.L.), and UG1 CA189859 (E.M.P.); the Henry Schueler 41&9 Foundation (C.G.M.); a St. Baldrick's Foundation Robert J. Arceci Innovation Award (to C.G.M.); a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (to S.K.); grants from the Wilson Centre for Blood Cancer Genomics (P.B.); the Snowdome Foundation (P.B.); the Peter MacCallum Cancer Foundation (G.L.R.); a SCOR Grant (7015-18); the Lymphoma and Leukemia Society (P.G.E.); the Perpetual Trustees and the Samuel Nissen Foundation (P.G.E.); and the National Health and Medical Research Council of Australia (A.O., GNT1140626). Funding Information: The authors thank the Haematology Tissue Bank (Peter MacCallum Cancer Centre/Royal Melbourne Hospital) and Children's Cancer Centre Tissue Bank (Murdoch Children's Research Institute) for assistance with sample collection and the Genomics Core Facility and Genomics Platform Group (University of Melbourne Centre for Cancer Research) for sequencing and analysis support. The authors are supported by the American and Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital; the St. Jude Children's Research Hospital Chromatin Collaborative (C.G.M.); National Institutes of Health National Cancer Institute (NCI) grants P30 CA021765, R35 CA197695 (C.G.M.), U10 CA180820 (ECOG-ACRIN), UG1 CA232760 (M.L.), and UG1 CA189859 (E.M.P.); the Henry Schueler 41&9 Foundation (C.G.M.); a St. Baldrick's Foundation Robert J. Arceci Innovation Award (to C.G.M.); a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (to S.K.); grants from the Wilson Centre for Blood Cancer Genomics (P.B.); the Snowdome Foundation (P.B.); the Peter MacCallum Cancer Foundation (G.L.R.); a SCOR Grant (7015-18); the Lymphoma and Leukemia Society (P.G.E.); the Perpetual Trustees and the Samuel Nissen Foundation (P.G.E.); and the National Health and Medical Research Council of Australia (A.O. GNT1140626). Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",
year = "2022",
month = jun,
day = "16",
doi = "10.1182/blood.2022015444",
language = "English (US)",
volume = "139",
pages = "3519--3531",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "24",
}