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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| Vydáno v: | Cancer discovery Ročník 11; číslo 11; s. 2846 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
United States
01.11.2021
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| Témata: | |
| ISSN: | 2159-8290, 2159-8290 |
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| 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
, 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.
. |
|---|---|
| AbstractList | 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.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. 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. . |
| Author | Westover, Tamara Kern, Wolfgang Relling, Mary V Luger, Selina Crews, Kristine R Yang, Jun J Yin, Jun Haferlach, Torsten Kornblau, Steven M Mead, Paul E Dickerson, Kirsten Wu, Gang Chen, Xiaolong den Boer, Monique L Wang, Victoria Paietta, Elisabeth M Hunger, Stephen P Pölönen, Petri Roberts, Kathryn G Chang, Ti-Cheng Rashkovan, Marissa Rowe, Jacob M Ma, Xiaotu Cheng, Zhongshan Valentine, Marcus B Mehr, Cyrus M Haferlach, Claudia Qu, Chunxu Zhang, Jinghui Garcia-Prat, Laura Yang, Wenjian Iacobucci, Ilaria Dick, John E Ferrando, Adolfo A Montefiori, Lindsey E Stengel, Anna Kimura, Shunsuke Gu, Zhaohui Xu, Beisi Stock, Wendy Klco, Jeffery M Pui, Ching-Hon Evans, William E Bendig, Sonja Abdelhamed, Sherif Murison, Alex Hiltenbrand, Ryan Ma, Jing Zeng, Andy Loh, Mignon L Litzow, Mark R Mullighan, Charles G |
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Xiaotu organization: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee – sequence: 7 givenname: Alex surname: Murison fullname: Murison, Alex organization: Department of Molecular Genetics, University of Toronto, Toronto, Canada – sequence: 8 givenname: Andy surname: Zeng fullname: Zeng, Andy organization: Department of Molecular Genetics, University of Toronto, Toronto, Canada – sequence: 9 givenname: Laura surname: Garcia-Prat fullname: Garcia-Prat, Laura organization: Department of Molecular Genetics, University of Toronto, Toronto, Canada – sequence: 10 givenname: Kirsten surname: Dickerson fullname: Dickerson, Kirsten organization: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee – sequence: 11 givenname: Ilaria surname: Iacobucci fullname: Iacobucci, Ilaria organization: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee – sequence: 12 givenname: Sherif orcidid: 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organization: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee – sequence: 24 givenname: Marcus B surname: Valentine fullname: Valentine, Marcus B organization: Cytogenetics Core Facility, St. Jude Children's Research Hospital, Memphis, Tennessee – sequence: 25 givenname: Marissa orcidid: 0000-0002-6990-8186 surname: Rashkovan fullname: Rashkovan, Marissa organization: Institute for Cancer Genetics, Columbia University, New York, New York – sequence: 26 givenname: Selina surname: Luger fullname: Luger, Selina organization: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania – sequence: 27 givenname: Mark R surname: Litzow fullname: Litzow, Mark R organization: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota – sequence: 28 givenname: Jacob M surname: Rowe fullname: Rowe, Jacob M organization: Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel – sequence: 29 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Canada – sequence: 50 givenname: Jeffery M orcidid: 0000-0003-2961-6960 surname: Klco fullname: Klco, Jeffery M email: charles.mullighan@stjude.org, Jeffery.klco@stjude.org, Claudia.haferlach@mll.com organization: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee. charles.mullighan@stjude.org Jeffery.klco@stjude.org Claudia.haferlach@mll.com – sequence: 51 givenname: Claudia surname: Haferlach fullname: Haferlach, Claudia email: charles.mullighan@stjude.org, Jeffery.klco@stjude.org, Claudia.haferlach@mll.com organization: Munich Leukemia Laboratory, Munich, Germany. charles.mullighan@stjude.org Jeffery.klco@stjude.org Claudia.haferlach@mll.com – sequence: 52 givenname: Charles G orcidid: 0000-0002-1871-1850 surname: Mullighan fullname: Mullighan, Charles G email: charles.mullighan@stjude.org, Jeffery.klco@stjude.org, Claudia.haferlach@mll.com organization: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee. 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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34103329$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | 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 |
| Title | Enhancer Hijacking Drives Oncogenic BCL11B Expression in Lineage-Ambiguous Stem Cell Leukemia |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/34103329 https://www.proquest.com/docview/2539527244 |
| Volume | 11 |
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