@article{fe07cdb2ab4c4b949c249f1067b594bd,
title = "Enhancer hijacking drives oncogenic bcl11b expression in lineage-ambiguous stem cell leukemia",
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.",
author = "Montefiori, {Lindsey E.} and Sonja Bendig and Zhaohui Gu and Xiaolong Chen and Petri P{\"o}l{\"o}nen and Xiaotu Ma and Alex Murison and Andy Zeng and Laura Garcia-Prat and Kirsten Dickerson and Ilaria Iacobucci and Sherif Abdelhamed and Ryan Hiltenbrand and Mead, {Paul E.} and Mehr, {Cyrus M.} and Beisi Xu and Zhongshan Cheng and Chang, {Ti Cheng} and Tamara Westover and Jing Ma and Anna Stengel and Shunsuke Kimura and Chunxu Qu and Valentine, {Marcus B.} and Marissa Rashkovan and Selina Luger and Litzow, {Mark R.} and Rowe, {Jacob M.} and {Den Boer}, {Monique L.} and Victoria Wang and Jun Yin and Kornblau, {Steven M.} and Hunger, {Stephen P.} and Loh, {Mignon L.} and Pui, {Ching Hon} and Wenjian Yang and Crews, {Kristine R.} and Roberts, {Kathryn G.} and Yang, {Jun J.} and Relling, {Mary V.} and Evans, {William E.} and Wendy Stock and Paietta, {Elisabeth M.} and Ferrando, {Adolfo A.} and Jinghui Zhang and Wolfgang Kern and Torsten Haferlach and Gang Wu and Dick, {John E.} and Klco, {Jeffery M.} and Claudia Haferlach and Mullighan, {Charles G.}",
note = "Funding Information: This study was supported by grants from the NIH R35 CA197695 and P30 CA021765 (to C.G. Mullighan), R01 CA216391 (to J. Zhang), R35 CA210065 and P30 CA103696 (to A.A. Ferrando), F32 CA254140 (to L.E. Montefiori), P50 GM115279-01 (to M.V. Relling and M.L. Loh), R00 CA241297 (to Z. Gu), The St. Jude Children{\textquoteright}s Research Hospital Chromatin Collaborative, the Henry Schueler 41&9 Foundation (to C.G. Mullighan), a St. Baldrick{\textquoteright}s Foundation Robert J. Arceci Innovation award (to C.G. Mullighan), an Alex{\textquoteright}s Lemonade Stand Foundation award (to C.G. Mullighan), a Burroughs Wellcome Fund Career Award for Medical Scientists (to J.M. Klco), and the Leukemia and Lymphoma Society{\textquoteright}s Career Development Program Special Fellow (to Z. Gu). This study was conducted in part by the ECOG–ACRIN Cancer Research Group (Peter J. O{\textquoteright}Dwyer, MD, and Mitchell D. Schnall, MD, PhD, group co-chairs) and supported by the NCI of the NIH under the following award numbers: U10CA180820, U10CA180794, UG1CA189859, UG1CA232760, UG1CA233234, UG1CA233290, U24CA196171, and U10CA180821 (to E.M. Paietta and M.R. Litzow). M. Rashkovan is a Damon Runyon-Sohn Pediatric Cancer Fellow supported by the Damon Runyon Cancer Research Foundation (DRSG-2017). This study was supported by funds to J.E. Dick from the Princess Margaret Cancer Centre through funding provided by Ontario Ministry of Health, Princess Margaret Cancer Centre Foundation, Ontario Institute for Cancer Research through funding provided by the Government of Ontario, Canadian Institutes for Health Research (RN380110-409786), Canadian Cancer Society (grant #703212), Terry Fox New Frontiers Program Project Grant, and a Canada Research Chair. Funding Information: S. Bendig reports personal fees from MLL Munich Leukemia Laboratory outside the submitted work. I. Iacobucci reports honoraria from Amgen although not relevant to the work here presented. A. Stengel reports personal fees from MLL Munich Leukemia Laboratory outside the submitted work. M. Rashkovan reports grants from Damon Runyon Cancer Research Foundation during the conduct of the study. S. Luger reports personal fees from Daiichi-Sankyo, Jazz, BMS, Agios, AbbVie, and Syros, grants from Biosgiht, Celgene, Hoffman LaRoche, and Kura outside the submitted work. V. Wang reports grants from NCI during the conduct of the study. M.L. Loh reports personal fees from MediSix Therapeutics outside the submitted work. C. Pui reports grants from NCI during the conduct of the study; personal fees from Adaptive Biotechnology Inc, from Novartis, Amgen, and Erytech outside the submitted work. M.V. Rel-ling reports grants from NIH/NCI/and grants and personal fees from Servier outside the submitted work; and Spouse on board of BioSk-ryb, Inc. and Scientific Advisory Board Chair of Princess M{\'a}xima Center. W.E. Evans reports grants from NIH/NCI outside the submitted work; and Board member of BioSkryb, Inc., scientific advisory board chair of Princess M{\'a}xima Center. A.A. Ferrando reports grants from NCI and grants from Alex Lemonade Stand Foundation during the conduct of the study; personal fees from Ayala Pharmaceuticals, Brystol Myers Squib SpringWorks Therapeutics, VantAI, grants from The Chemotherapy Foundation, Hyundai, Leukemia and Lymphoma Society, and Pershing Square Sohn Cancer Research Alliance, and other support from the American Society of Hematology outside the submitted work. J.E. Dick reports grants from Celgene-BMS and other support from Trillium Therapeutics Inc outside the submitted work. C. Haferlach reports other support from MLL Munich Leukemia Laboratory outside the submitted work. C.G. Mullighan reports personal fees from Illumina during the conduct of the study; grants from AbbVie and Pfizer, and other support from Amgen outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2021",
month = nov,
doi = "10.1158/2159-8290.CD-21-0145",
language = "English (US)",
volume = "11",
pages = "2846--2867",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "11",
}