Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/135848
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Type: Journal article
Title: Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia
Author: Kimura, S.
Montefiori, L.
Iacobucci, I.
Zhao, Y.
Gao, Q.
Paietta, E.M.
Haferlach, C.
Laird, A.D.
Mead, P.E.
Gu, Z.
Stock, W.
Litzow, M.R.
Rowe, J.M.
Luger, S.M.
Hunger, S.P.
Ryland, G.
Schmidt, B.M.
Ekert, P.G.
Oshlack, A.
Grimmond, S.
et al.
Citation: Blood, 2022; 139(24):3519-3531
Publisher: American Society of Hematology
Issue Date: 2022
ISSN: 0006-4971
1528-0020
Statement of
Responsibility: 
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
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.
Keywords: Chromatin
Humans
Pol1 Transcription Initiation Complex Proteins
Transcription Factors
Prognosis
Genomics
Adolescent
Adult
Aged
Middle Aged
Child
Female
Male
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Young Adult
Transcriptome
CDX2 Transcription Factor
Rights: © 2022 by The American Society of Hematology
DOI: 10.1182/blood.2022015444
Published version: http://dx.doi.org/10.1182/blood.2022015444
Appears in Collections:Medicine publications

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