The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops

Sophie Ottema; Roger Mulet-Lazaro; Claudia Erpelinck-Verschueren; Stanley van Herk; Marije Havermans; Andrea Arricibita Varea; Michael Vermeulen; H. Berna Beverloo; Stefan Gröschel; Torsten Haferlach; Claudia Haferlach; Bas J. Wouters; Eric Bindels; Leonie Smeenk; Ruud Delwel

doi:10.1038/s41467-021-25862-3

The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops

Sophie Ottema, Roger Mulet-Lazaro, Claudia Erpelinck-Verschueren, Stanley van Herk, Marije Havermans, Andrea Arricibita Varea, Michael Vermeulen, H. Berna Beverloo, Stefan Gröschel, Torsten Haferlach, Claudia Haferlach, Bas J. Wouters, Eric Bindels, Leonie Smeenk, Ruud Delwel^*

^*Corresponding author for this work

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

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Abstract

Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements, which is often therapy resistant. In AMLs harboring a t(3;8)(q26;q24), we observed the translocation of a MYC super-enhancer (MYC SE) to the EVI1 locus. We generated an in vitro model mimicking a patient-based t(3;8)(q26;q24) using CRISPR-Cas9 technology and demonstrated hyperactivation of EVI1 by the hijacked MYC SE. This MYC SE contains multiple enhancer modules, of which only one recruits transcription factors active in early hematopoiesis. This enhancer module is critical for EVI1 overexpression as well as enhancer-promoter interaction. Multiple CTCF binding regions in the MYC SE facilitate this enhancer-promoter interaction, which also involves a CTCF binding site upstream of the EVI1 promoter. We hypothesize that this CTCF site acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of other 3q26-rearranged AML patient cells point to a common mechanism by which EVI1 uses this docking site to hijack enhancers active in early hematopoiesis.

Original language	English
Article number	5679
Number of pages	13
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25862-3
Publication status	Published - 28 Sept 2021

Bibliographical note

Acknowledgements:
The authors are indebted to their colleagues from the bone marrow transplantation group and the molecular and cytogenetics diagnostics laboratories of the Department of Hematology and Clinical Genetics at Erasmus University Medical Center for storage of samples and molecular analysis of the leukemia cells (M. Wattel, R. van der Helm, and P.J.M. Valk). For providing patient material, the authors are thankful to the MLL Münchner Leukämielabor GmbH in Germany. They also thank P. Sonneveld and their colleagues of the Hematology Department, especially those involved in FACS sorting (C. van Dijk), Next Generation Sequencing operating bioinformatics (R. Hoogenboe-zem), and all others for their input or expertise. We also thank N.J. Galjart and R. Stadhouders of the department of Cell Biology and Pulmonary medicine at the Erasmus University Medical Center for their input and expertise. This work was funded by grants and fellowships from the Dutch Cancer Society (R.D., R.M.-L., S.O., L.S.), Skyline DX (S.O.), the Daniel den Hoed, Erasmus MC Foundation (L.S.).

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© 2021, The Author(s).

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Ottema, S., Mulet-Lazaro, R., Erpelinck-Verschueren, C., van Herk, S., Havermans, M., Arricibita Varea, A., Vermeulen, M., Beverloo, H. B., Gröschel, S., Haferlach, T., Haferlach, C., J. Wouters, B., Bindels, E., Smeenk, L., & Delwel, R. (2021). The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops. Nature Communications, 12(1), [5679]. https://doi.org/10.1038/s41467-021-25862-3

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title = "The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops",

abstract = "Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements, which is often therapy resistant. In AMLs harboring a t(3;8)(q26;q24), we observed the translocation of a MYC super-enhancer (MYC SE) to the EVI1 locus. We generated an in vitro model mimicking a patient-based t(3;8)(q26;q24) using CRISPR-Cas9 technology and demonstrated hyperactivation of EVI1 by the hijacked MYC SE. This MYC SE contains multiple enhancer modules, of which only one recruits transcription factors active in early hematopoiesis. This enhancer module is critical for EVI1 overexpression as well as enhancer-promoter interaction. Multiple CTCF binding regions in the MYC SE facilitate this enhancer-promoter interaction, which also involves a CTCF binding site upstream of the EVI1 promoter. We hypothesize that this CTCF site acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of other 3q26-rearranged AML patient cells point to a common mechanism by which EVI1 uses this docking site to hijack enhancers active in early hematopoiesis.",

author = "Sophie Ottema and Roger Mulet-Lazaro and Claudia Erpelinck-Verschueren and {van Herk}, Stanley and Marije Havermans and {Arricibita Varea}, Andrea and Michael Vermeulen and Beverloo, {H. Berna} and Stefan Gr{\"o}schel and Torsten Haferlach and Claudia Haferlach and {J. Wouters}, Bas and Eric Bindels and Leonie Smeenk and Ruud Delwel",

note = "Acknowledgements: The authors are indebted to their colleagues from the bone marrow transplantation group and the molecular and cytogenetics diagnostics laboratories of the Department of Hematology and Clinical Genetics at Erasmus University Medical Center for storage of samples and molecular analysis of the leukemia cells (M. Wattel, R. van der Helm, and P.J.M. Valk). For providing patient material, the authors are thankful to the MLL M{\"u}nchner Leuk{\"a}mielabor GmbH in Germany. They also thank P. Sonneveld and their colleagues of the Hematology Department, especially those involved in FACS sorting (C. van Dijk), Next Generation Sequencing operating bioinformatics (R. Hoogenboe-zem), and all others for their input or expertise. We also thank N.J. Galjart and R. Stadhouders of the department of Cell Biology and Pulmonary medicine at the Erasmus University Medical Center for their input and expertise. This work was funded by grants and fellowships from the Dutch Cancer Society (R.D., R.M.-L., S.O., L.S.), Skyline DX (S.O.), the Daniel den Hoed, Erasmus MC Foundation (L.S.). Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41467-021-25862-3",

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Ottema, S , Mulet-Lazaro, R , Erpelinck-Verschueren, C , van Herk, S, Havermans, M, Arricibita Varea, A, Vermeulen, M , Beverloo, HB, Gröschel, S, Haferlach, T, Haferlach, C, J. Wouters, B , Bindels, E , Smeenk, L & Delwel, R 2021, 'The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops', Nature Communications, vol. 12, no. 1, 5679. https://doi.org/10.1038/s41467-021-25862-3

TY - JOUR

T1 - The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops

AU - Ottema, Sophie

AU - Mulet-Lazaro, Roger

AU - Erpelinck-Verschueren, Claudia

AU - van Herk, Stanley

AU - Havermans, Marije

AU - Arricibita Varea, Andrea

AU - Vermeulen, Michael

AU - Beverloo, H. Berna

AU - Gröschel, Stefan

AU - Haferlach, Torsten

AU - Haferlach, Claudia

AU - J. Wouters, Bas

AU - Bindels, Eric

AU - Smeenk, Leonie

AU - Delwel, Ruud

N1 - Acknowledgements: The authors are indebted to their colleagues from the bone marrow transplantation group and the molecular and cytogenetics diagnostics laboratories of the Department of Hematology and Clinical Genetics at Erasmus University Medical Center for storage of samples and molecular analysis of the leukemia cells (M. Wattel, R. van der Helm, and P.J.M. Valk). For providing patient material, the authors are thankful to the MLL Münchner Leukämielabor GmbH in Germany. They also thank P. Sonneveld and their colleagues of the Hematology Department, especially those involved in FACS sorting (C. van Dijk), Next Generation Sequencing operating bioinformatics (R. Hoogenboe-zem), and all others for their input or expertise. We also thank N.J. Galjart and R. Stadhouders of the department of Cell Biology and Pulmonary medicine at the Erasmus University Medical Center for their input and expertise. This work was funded by grants and fellowships from the Dutch Cancer Society (R.D., R.M.-L., S.O., L.S.), Skyline DX (S.O.), the Daniel den Hoed, Erasmus MC Foundation (L.S.). Publisher Copyright: © 2021, The Author(s).

PY - 2021/9/28

Y1 - 2021/9/28

N2 - Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements, which is often therapy resistant. In AMLs harboring a t(3;8)(q26;q24), we observed the translocation of a MYC super-enhancer (MYC SE) to the EVI1 locus. We generated an in vitro model mimicking a patient-based t(3;8)(q26;q24) using CRISPR-Cas9 technology and demonstrated hyperactivation of EVI1 by the hijacked MYC SE. This MYC SE contains multiple enhancer modules, of which only one recruits transcription factors active in early hematopoiesis. This enhancer module is critical for EVI1 overexpression as well as enhancer-promoter interaction. Multiple CTCF binding regions in the MYC SE facilitate this enhancer-promoter interaction, which also involves a CTCF binding site upstream of the EVI1 promoter. We hypothesize that this CTCF site acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of other 3q26-rearranged AML patient cells point to a common mechanism by which EVI1 uses this docking site to hijack enhancers active in early hematopoiesis.

AB - Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements, which is often therapy resistant. In AMLs harboring a t(3;8)(q26;q24), we observed the translocation of a MYC super-enhancer (MYC SE) to the EVI1 locus. We generated an in vitro model mimicking a patient-based t(3;8)(q26;q24) using CRISPR-Cas9 technology and demonstrated hyperactivation of EVI1 by the hijacked MYC SE. This MYC SE contains multiple enhancer modules, of which only one recruits transcription factors active in early hematopoiesis. This enhancer module is critical for EVI1 overexpression as well as enhancer-promoter interaction. Multiple CTCF binding regions in the MYC SE facilitate this enhancer-promoter interaction, which also involves a CTCF binding site upstream of the EVI1 promoter. We hypothesize that this CTCF site acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of other 3q26-rearranged AML patient cells point to a common mechanism by which EVI1 uses this docking site to hijack enhancers active in early hematopoiesis.

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U2 - 10.1038/s41467-021-25862-3

DO - 10.1038/s41467-021-25862-3

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The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops

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