Kimura, Shunsuke
https://orcid.org/0000-0002-2158-467X
Mayo Clinic
St. Jude Children's Research Hospital
Citations 2
Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia
Kimura, Shunsuke , Montefiori, Lindsey E. , Zhao, Yaqi , Gao, Qingsong , Paietta, Elisabeth , Mead, Paul E., Gu, Zhaohui , Litzow, Mark R. , Rowe, Jacob M. , Luger, Selina M. , Schmidt, Breon , Ekert, Paul G. , Oshlack, Alicia , Grimmond, Sean M. , Rehn, Jacqueline , Breen, James , Meggendorfer, Manja , Walter, Wencke , Kern, Wolfgang , Haferlach, Torsten , Brady, Samuel W. , Zhang, Jinghui , Blombery, Piers , Montefiori, Lindsey , Zhao, Yaqi , Gao, Qingsong , Gu, Zhaohui , Litzow, Mark R. , Hunger, Stephen P , Ryland, Georgina L , Oshlack, Alicia , Grimmond, Sean M , Rehn, Jacqueline , Yeung, David , White, Deborah L , Pui, Ching-Hon , Walter, Wencke , Roberts, Kathryn G , Mullighan, Charles G , Kimura, Shunsuke , Kern, Wolfgang , Iacobucci, Ilaria , Haferlach, Claudia , Laird, Alexander , Stock, Wendy , Hunger, Stephen P. , Aldoss, Ibrahim , Jabbour, Elias , Roberts, Kathryn G. , Mullighan, Charles G.
Blood | February 22, 2022 | Volume: 139 | Issue: 24 | Pages: 3519-3531
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.
Enhancer Hijacking Drives Oncogenic BCL11B Expression in Lineage-Ambiguous Stem Cell Leukemia
Bendig, Sonja , Gu, Zhaohui , Chen, Xiaolong , Ma, Xiaotu , Murison, Alex, Zeng, Andy G.X. , Dickerson, Kirsten , Mead, Paul E., Mehr, Cyrus M., Xu, Beisi , Cheng, Zhongshan , Chang, Ti‐Cheng , Westover, Tamara , Ma, Jing , Stengel, Anna , Kimura, Shunsuke , Valentine, Marcus B., Rashkovan, Marissa , Luger, Selina M. , Litzow, Mark R. , Rowe, Jacob M. , Wang, Victoria , Yin, Jun , Loh, Mignon L. , Crews, Kristine R. , Relling, Mary V. , Evans, William E. , Paietta, Elisabeth , Ferrando, Adolfo A. , Zhang, Jinghui , Kern, Wolfgang , Haferlach, Torsten , Dick, John E. , Klco, Jeffery M. , Gu, Zhaohui , Chen, Xiaolong , Ma, Xiaotu , Abdelhamed, Sherif , Xu, Beisi , Kimura, Shunsuke , Rashkovan, Marissa , den Boer, Monique L , Yin, Jun , Hunger, Stephen P , Pui, Ching-Hon , Yang, Wenjian , Crews, Kristine R , Roberts, Kathryn G , Stock, Wendy , Zhang, Jinghui , Dick, John E , Klco, Jeffery M , Mullighan, Charles G , Loh, Mignon L , Kern, Wolfgang , Montefiori, Lindsey E. , Pölönen, Petri , García‐Prat, Laura , Iacobucci, Ilaria , Hiltenbrand, Ryan , Qu, Chunxu , Kornblau, Steven M. , Hunger, Stephen P. , Yang, Wenjian , Roberts, Kathryn G. , Yang, Jun J.J. , Stock, Wendy , Wu, Gang , Haferlach, Claudia , Mullighan, Charles G.
Cancer Discovery | June 8, 2021 | Volume: 11 | Issue: 11 | Pages: 2846-2867
Abstract Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of BCL11B, a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose BCL11B to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to BCL11B. Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed BCL11B allele and association of BCL11B with activated hematopoietic progenitor cell cis-regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic BCL11B expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. Significance: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of BCL11B driven by diverse structural alterations, including de novo superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries. This article is highlighted in the In This Issue feature, p. 2659