Enhancer hijacking drives oncogenic bcl11b expression in lineage-ambiguous stem cell leukemia

Lindsey E. Montefiori, Sonja Bendig, Zhaohui Gu, Xiaolong Chen, Petri Pölönen, Xiaotu Ma, Alex Murison, Andy Zeng, Laura Garcia-Prat, Kirsten Dickerson, Ilaria Iacobucci, Sherif Abdelhamed, Ryan Hiltenbrand, Paul E. Mead, Cyrus M. Mehr, Beisi Xu, Zhongshan Cheng, Ti Cheng Chang, Tamara Westover, Jing MaAnna Stengel, Shunsuke Kimura, Chunxu Qu, Marcus B. Valentine, Marissa Rashkovan, Selina Luger, Mark R. Litzow, Jacob M. Rowe, Monique L. Den Boer, Victoria Wang, Jun Yin, Steven M. Kornblau, Stephen P. Hunger, Mignon L. Loh, Ching Hon Pui, Wenjian Yang, Kristine R. Crews, Kathryn G. Roberts, Jun J. Yang, Mary V. Relling, William E. Evans, Wendy Stock, Elisabeth M. Paietta, Adolfo A. Ferrando, Jinghui Zhang, Wolfgang Kern, Torsten Haferlach, Gang Wu, John E. Dick, Jeffery M. Klco, Claudia Haferlach, Charles G. Mullighan

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2846-2867
Number of pages22
JournalCancer discovery
Volume11
Issue number11
DOIs
StatePublished - Nov 2021

ASJC Scopus subject areas

  • Oncology

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