Enhancer hijacking drives oncogenic bcl11b expression in lineage-ambiguous stem cell leukemia

Lindsey E. Montefiori; Sonja Bendig; Zhaohui Gu; Xiaolong Chen; Petri Pölönen; Xiaotu Ma; Alex Murison; Andy Zeng; Laura Garcia-Prat; 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 Luger; Mark R. Litzow; Jacob M. Rowe; Monique L. Den Boer; Victoria Wang; Jun Yin; Steven M. Kornblau; Stephen P. Hunger; Mignon L. Loh; Ching Hon Pui; Wenjian Yang; Kristine R. Crews; Kathryn G. Roberts; Jun J. Yang; Mary V. Relling; William E. Evans; Wendy Stock; Elisabeth M. Paietta; Adolfo A. Ferrando; Jinghui Zhang; Wolfgang Kern; Torsten Haferlach; Gang Wu; John E. Dick; Jeffery M. Klco; Claudia Haferlach; Charles G. Mullighan

doi:10.1158/2159-8290.CD-21-0145

Enhancer hijacking drives oncogenic bcl11b expression in lineage-ambiguous stem cell leukemia

Lindsey E. Montefiori, Sonja Bendig, Zhaohui Gu, Xiaolong Chen, Petri Pölönen, Xiaotu Ma, Alex Murison, Andy Zeng, Laura Garcia-Prat, Kirsten Dickerson, Ilaria Iacobucci, Sherif Abdelhamed, Ryan Hiltenbrand, Paul E. Mead, Cyrus M. Mehr, Beisi Xu, Zhongshan Cheng, Ti Cheng Chang, Tamara Westover, Jing MaAnna Stengel, Shunsuke Kimura, Chunxu Qu, Marcus B. Valentine, Marissa Rashkovan, Selina Luger, Mark R. Litzow, Jacob M. Rowe, Monique L. Den Boer, Victoria Wang, Jun Yin, Steven M. Kornblau, Stephen P. Hunger, Mignon L. Loh, Ching Hon Pui, Wenjian Yang, Kristine R. Crews, Kathryn G. Roberts, Jun J. Yang, Mary V. Relling, William E. Evans, Wendy Stock, Elisabeth M. Paietta, Adolfo A. Ferrando, Jinghui Zhang, Wolfgang Kern, Torsten Haferlach, Gang Wu, John E. Dick, Jeffery M. Klco, Claudia Haferlach, Charles G. Mullighan

Oncology

Research output: Contribution to journal › Article › peer-review

69 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2846-2867
Number of pages	22
Journal	Cancer discovery
Volume	11
Issue number	11
DOIs	https://doi.org/10.1158/2159-8290.CD-21-0145
State	Published - Nov 2021

ASJC Scopus subject areas

Oncology

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Montefiori, L. E., Bendig, S., Gu, Z., Chen, X., Pölönen, P., Ma, X., Murison, A., Zeng, A., Garcia-Prat, L., Dickerson, K., Iacobucci, I., Abdelhamed, S., Hiltenbrand, R., Mead, P. E., Mehr, C. M., Xu, B., Cheng, Z., Chang, T. C., Westover, T., ... Mullighan, C. G. (2021). Enhancer hijacking drives oncogenic bcl11b expression in lineage-ambiguous stem cell leukemia. Cancer discovery, 11(11), 2846-2867. https://doi.org/10.1158/2159-8290.CD-21-0145

Montefiori, LE, Bendig, S, Gu, Z, Chen, X, Pölönen, P, Ma, X, Murison, A, Zeng, A, Garcia-Prat, L, Dickerson, K, Iacobucci, I, Abdelhamed, S, Hiltenbrand, R, Mead, PE, Mehr, CM, Xu, B, Cheng, Z, Chang, TC, Westover, T, Ma, J, Stengel, A, Kimura, S, Qu, C, Valentine, MB, Rashkovan, M, Luger, S, Litzow, MR, Rowe, JM, Den Boer, ML, Wang, V, Yin, J, Kornblau, SM, Hunger, SP, Loh, ML, Pui, CH, Yang, W, Crews, KR, Roberts, KG, Yang, JJ, Relling, MV, Evans, WE, Stock, W, Paietta, EM, Ferrando, AA, Zhang, J, Kern, W, Haferlach, T, Wu, G, Dick, JE, Klco, JM, Haferlach, C & Mullighan, CG 2021, 'Enhancer hijacking drives oncogenic bcl11b expression in lineage-ambiguous stem cell leukemia', Cancer discovery, vol. 11, no. 11, pp. 2846-2867. https://doi.org/10.1158/2159-8290.CD-21-0145

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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 = "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",

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T1 - Enhancer hijacking drives oncogenic bcl11b expression in lineage-ambiguous stem cell leukemia

AU - Montefiori, Lindsey E.

AU - Bendig, Sonja

AU - Gu, Zhaohui

AU - Chen, Xiaolong

AU - Pölönen, Petri

AU - Ma, Xiaotu

AU - Murison, Alex

AU - Zeng, Andy

AU - Garcia-Prat, Laura

AU - Dickerson, Kirsten

AU - Iacobucci, Ilaria

AU - Abdelhamed, Sherif

AU - Hiltenbrand, Ryan

AU - Mead, Paul E.

AU - Mehr, Cyrus M.

AU - Xu, Beisi

AU - Cheng, Zhongshan

AU - Chang, Ti Cheng

AU - Westover, Tamara

AU - Ma, Jing

AU - Stengel, Anna

AU - Kimura, Shunsuke

AU - Qu, Chunxu

AU - Valentine, Marcus B.

AU - Rashkovan, Marissa

AU - Luger, Selina

AU - Litzow, Mark R.

AU - Rowe, Jacob M.

AU - Den Boer, Monique L.

AU - Wang, Victoria

AU - Yin, Jun

AU - Kornblau, Steven M.

AU - Hunger, Stephen P.

AU - Loh, Mignon L.

AU - Pui, Ching Hon

AU - Yang, Wenjian

AU - Crews, Kristine R.

AU - Roberts, Kathryn G.

AU - Yang, Jun J.

AU - Relling, Mary V.

AU - Evans, William E.

AU - Stock, Wendy

AU - Paietta, Elisabeth M.

AU - Ferrando, Adolfo A.

AU - Zhang, Jinghui

AU - Kern, Wolfgang

AU - Haferlach, Torsten

AU - Wu, Gang

AU - Dick, John E.

AU - Klco, Jeffery M.

AU - Haferlach, Claudia

AU - Mullighan, Charles G.

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

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ER -

Enhancer hijacking drives oncogenic bcl11b expression in lineage-ambiguous stem cell leukemia

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