| Literature DB >> 34103329 |
Lindsey E Montefiori1, Sonja Bendig2, Zhaohui Gu3,4, Xiaolong Chen5, Petri Pölönen1, Xiaotu Ma5, Alex Murison6, Andy Zeng6, Laura Garcia-Prat6, Kirsten Dickerson1, Ilaria Iacobucci1, Sherif Abdelhamed1, Ryan Hiltenbrand1, Paul E Mead1, Cyrus M Mehr1, Beisi Xu7, Zhongshan Cheng7, Ti-Cheng Chang7, Tamara Westover1, Jing Ma1, Anna Stengel2, Shunsuke Kimura1, Chunxu Qu1, Marcus B Valentine8, Marissa Rashkovan9, Selina Luger10, Mark R Litzow11, Jacob M Rowe12, Monique L den Boer13, Victoria Wang14, Jun Yin15, Steven M Kornblau16, Stephen P Hunger17, Mignon L Loh18, Ching-Hon Pui19, Wenjian Yang20, Kristine R Crews20, Kathryn G Roberts1, Jun J Yang20, Mary V Relling20, William E Evans20, Wendy Stock21, Elisabeth M Paietta22, Adolfo A Ferrando9,23,24,25, Jinghui Zhang5, Wolfgang Kern2, Torsten Haferlach2, Gang Wu1,7, John E Dick6, Jeffery M Klco26, Claudia Haferlach27, Charles G Mullighan26.
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. ©2021 American Association for Cancer Research.Entities:
Mesh：
Substances：
Year: 2021 PMID： 34103329 PMCID： PMC8563395 DOI： 10.1158/2159-8290.CD-21-0145
Source DB: PubMed Journal: Cancer Discov ISSN： 2159-8274 Impact factor: 39.397