Open AccessEnhancer Hijacking Drives Oncogenic BCL11B Expression in Lineage-Ambiguous Stem Cell Leukemia
Author(s) -
Lindsey Montefiori,
Sonja Bendig,
Zhaohui Gu,
Xiaolong Chen,
Petri Pölönen,
Xiaotu Ma,
Alex Murison,
Andy G.X. Zeng,
Laura GarcíaPrat,
Kirsten Dickerson,
Ilaria Iacobucci,
Sherif Abdelhamed,
Ryan Hiltenbrand,
Paul E. Mead,
Cyrus M. Mehr,
Beisi Xu,
Zhongshan Cheng,
Ti-Cheng Chang,
Tamara Westover,
Jing Ma,
Anna Stengel,
Shunsuke Kimura,
Chunxu Qu,
Marcus B. Valentine,
Marissa Rashkovan,
Selina M. Luger,
Mark R. Litzow,
Jacob M. Rowe,
Monique L. Den Boer,
Victoria Wang,
Jun Yin,
Steven M. Kornblau,
Stephen P. Hunger,
Mig L. Loh,
ChingHon Pui,
Wenjian Yang,
Kristine R. Crews,
Kathryn G. Roberts,
Jun J. Yang,
Mary V. Relling,
William E. Evans,
Wendy Stock,
Elisabeth Paietta,
Adolfo A. Ferrando,
Jinghui Zhang,
Wolfgang Kern,
Torsten Haferlach,
Gang Wu,
John E. Dick,
Jeffery M. Klco,
Claudia Haferlach,
Charles G. Mullighan
Publication year - 2021
Publication title -
cancer discovery
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.795
H-Index - 163
eISSN - 2159-8290
pISSN - 2159-8274
DOI - 10.1158/2159-8290.cd-21-0145
Subject(s) - biology , ectopic expression , cancer research , enhancer , transcription factor , haematopoiesis , progenitor cell , chromatin , leukemia , lineage (genetic) , stem cell , genetics , microbiology and biotechnology , gene
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 .