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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)2846-2867
Aantal pagina's22
TijdschriftCancer discovery
Volume11
Nummer van het tijdschrift11
DOI's
StatusGepubliceerd - nov. 2021

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