Enhancer Hijacking Drives Oncogenic BCL11B Expression in Lineage-Ambiguous Stem Cell Leukemia

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 , a master transcription factor responsi...

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Veröffentlicht in:	Cancer discovery Jg. 11; H. 11; S. 2846
Hauptverfasser:	Montefiori, Lindsey E, Bendig, Sonja, Gu, Zhaohui, Chen, Xiaolong, Pölönen, Petri, Ma, Xiaotu, Murison, Alex, Zeng, Andy, Garcia-Prat, Laura, Dickerson, Kirsten, Iacobucci, Ilaria, Abdelhamed, Sherif, Hiltenbrand, Ryan, Mead, Paul E, Mehr, Cyrus M, Xu, Beisi, Cheng, Zhongshan, Chang, Ti-Cheng, Westover, Tamara, Ma, Jing, Stengel, Anna, Kimura, Shunsuke, Qu, Chunxu, Valentine, Marcus B, Rashkovan, Marissa, Luger, Selina, Litzow, Mark R, Rowe, Jacob M, den Boer, Monique L, Wang, Victoria, Yin, Jun, Kornblau, Steven M, Hunger, Stephen P, Loh, Mignon L, Pui, Ching-Hon, Yang, Wenjian, Crews, Kristine R, Roberts, Kathryn G, Yang, Jun J, Relling, Mary V, Evans, William E, Stock, Wendy, Paietta, Elisabeth M, Ferrando, Adolfo A, Zhang, Jinghui, Kern, Wolfgang, Haferlach, Torsten, Wu, Gang, Dick, John E, Klco, Jeffery M, Haferlach, Claudia, Mullighan, Charles G
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 01.11.2021
Schlagworte:	Enhancer Elements, Genetic Gene Regulatory Networks Hematopoietic Stem Cells - metabolism Humans Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism Repressor Proteins - biosynthesis Repressor Proteins - genetics Repressor Proteins - metabolism Transcription Factors - genetics Tumor Suppressor Proteins - biosynthesis Tumor Suppressor Proteins - genetics
ISSN:	2159-8290, 2159-8290
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Zusammenfassung:	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 , a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to . Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed allele and association of with activated hematopoietic progenitor cell -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 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 driven by diverse structural alterations, including superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries. .
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2159-8290 2159-8290
DOI:	10.1158/2159-8290.CD-21-0145