Citations 1
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