Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia

Kimura, S; Montefiori, L; Iacobucci, I; Zhao, Y; Gao, Q; Paietta, EM; Haferlach, C; Laird, AD; Mead, PE; Gu, Z; Stock, W; Litzow, M; Rowe, JM; Luger, SM; Hunger, SP; Ryland, GL; Schmidt, B; Ekert, PG; Oshlack, A; Grimmond, SM; Rehn, J; Breen, J; Yeung, D; White, DL; Aldoss, I; Jabbour, EJ; Pui, CH; Meggendorfer, M; Walter, W; Kern, W; Haferlach, T; Brady, S; Zhang, J; Roberts, KG; Blombery, P; Mullighan, CG

Author(s): Kimura, S; Montefiori, L; Iacobucci, I; Zhao, Y; Gao, Q; Paietta, EM; Haferlach, C; Laird, AD; Mead, PE; Gu, Z; Stock, W; Litzow, M; Rowe, JM; Luger, SM; Hunger, SP; Ryland, GL; Schmidt, B; Ekert, PG; Oshlack, A; Grimmond, SM; Rehn, J; Breen, J; Yeung, D; White, DL; Aldoss, I; Jabbour, EJ; Pui, CH; Meggendorfer, M; Walter, W; Kern, W; Haferlach, T; Brady, S; Zhang, J; Roberts, KG; Blombery, P; Mullighan, CG;
Details: Publication Year 2022-06-16,Volume 139,Issue #24,Page 3519-3531
Journal Title: Blood
Publication Type: Research article
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: Adolescent; Adult; Aged; CDX2 Transcription Factor/genetics; Child; Chromatin; Female; Genomics/methods; Humans; Male; Middle Aged; Pol1 Transcription Initiation Complex Proteins; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis/genetics; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics; Prognosis; Transcription Factors/genetics; Transcriptome; Young Adult
Department(s): Pathology; Laboratory Research; Haematology
PubMed ID: 35192684
Publisher's Version: https://doi.org/10.1182/blood.2022015444
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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