Core-binding factor leukemia hijacks the T-cell–prone PU.1 antisense promoter

E. van der Kouwe; G. Heller; A. Czibere; J. A. Pulikkan; C. Agreiter; L. H. Castilla; R. Delwel; A. Di Ruscio; A. K. Ebralidze; M. Forte; F. Grebien; E. Heyes; L. Kazianka; J. Klinger; C. Kornauth; T. Le; K. Lind; I. A.M. Barbosa; T. Pemovska; A. Pichler; A. S. Schmolke; C. M. Schweicker; H. Sill; W. R. Sperr; A. Spittler; S. Surapally; B. Q. Trinh; P. Valent; K. Vanura; R. S. Welner; J. Zuber; D. G. Tenen; P. B. Staber

doi:10.1182/blood.2020008971

Core-binding factor leukemia hijacks the T-cell–prone PU.1 antisense promoter

E. van der Kouwe, G. Heller, A. Czibere, J. A. Pulikkan, C. Agreiter, L. H. Castilla, R. Delwel, A. Di Ruscio, A. K. Ebralidze, M. Forte, F. Grebien, E. Heyes, L. Kazianka, J. Klinger, C. Kornauth, T. Le, K. Lind, I. A.M. Barbosa, T. Pemovska, A. PichlerA. S. Schmolke, C. M. Schweicker, H. Sill, W. R. Sperr, A. Spittler, S. Surapally, B. Q. Trinh, P. Valent, K. Vanura, R. S. Welner, J. Zuber, D. G. Tenen, P. B. Staber^*

^*Corresponding author for this work

Hematology

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

11 Citations (Scopus)

Abstract

The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of crucial transcription factors. One of the key master regulators in the hematopoietic systems is PU.1. Reduced levels of PU.1 are characteristic for human acute myeloid leukemia (AML) and are known to induce AML in mouse models. Here, we show that transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core-binding factor (CBF) fusions RUNX1-ETO and CBFβ-MYH11 in t(8;21) and inv(16) AML, respectively, activate the PU.1 antisense promoter that results in a shift from sense toward antisense transcription and myeloid differentiation blockade. In patients with CBF-AML, we found that an elevated antisense/sense transcript and promoter accessibility ratio represents a hallmark compared with normal karyotype AML or healthy CD34⁺ cells. Competitive interaction of an enhancer with the proximal or the antisense promoter forms a binary on/off switch for either myeloid or T-cell development. Leukemic CBF fusions thus use a physiological mechanism used by T cells to decrease sense transcription. Our study is the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. Hence, this disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.

Original language	English
Pages (from-to)	1345-1358
Number of pages	14
Journal	Blood
Volume	138
Issue number	15
DOIs	https://doi.org/10.1182/blood.2020008971
Publication status	Published - 14 Oct 2021

Bibliographical note

Funding Information:
The authors acknowledge the Core Facilities of the Medical University of Vienna. The authors acknowledge the Biomedical Sequencing Facility, Center for Molecular Medicine (CeMM). A.D.R. was supported by grants from the National Institutes of Health (NIH), National Cancer Institute (R00CA188595), the Department of Defense (award number W81XWH-20-1-0518), Fondazione Cariplo N. 2016-0476, and the Giovanni Armenise-Harvard Foundation. A.K.E. was supported by the NIH, National Cancer Institute (R50 CA211304); P.V. was supported by the Austrian Science Fund (SFB grant F4704-B20). B.Q.T. is supported by the NIH, National Cancer Institute (K01CA222707). D.G.T. was supported by the NIH, National Cancer Institute (R35CA197697) and the National Heart, Lung, and Blood Institute (P01HL131477), and by the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award, and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.? P.B.S. received funding from the Austrian Science Fund (grant P27132-B20) and the Anniversary Fund of the Oesterreichische Nationalbank (grant P15936).

Funding Information:
A.D.R. was supported by grants from the National Institutes of Health (NIH), National Cancer Institute (R00CA188595), the Department of Defense (award number W81XWH-20-1-0518), Fondazione Cariplo N. 2016-0476, and the Giovanni Armenise-Harvard Foundation. A.K.E. was supported by the NIH, National Cancer Institute (R50 CA211304); P.V. was supported by the Austrian Science Fund (SFB grant F4704-B20). B.Q.T. is supported by the NIH, National Cancer Institute (K01CA222707). D.G.T. was supported by the NIH, National Cancer Institute (R35CA197697) and the National Heart, Lung, and Blood Institute (P01HL131477), and by the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award, and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.” P.B.S. received funding from the Austrian Science Fund (grant P27132-B20) and the Anniversary Fund of the Oesterreichische Nationalbank (grant P15936).

Publisher Copyright:
© 2021 American Society of Hematology

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van der Kouwe, E., Heller, G., Czibere, A., Pulikkan, J. A., Agreiter, C., Castilla, L. H., Delwel, R., Di Ruscio, A., Ebralidze, A. K., Forte, M., Grebien, F., Heyes, E., Kazianka, L., Klinger, J., Kornauth, C., Le, T., Lind, K., Barbosa, I. A. M., Pemovska, T., ... Staber, P. B. (2021). Core-binding factor leukemia hijacks the T-cell–prone PU.1 antisense promoter. Blood, 138(15), 1345-1358. https://doi.org/10.1182/blood.2020008971

@article{94395e4f0e5a4c7a87531a32bfb2738c,

title = "Core-binding factor leukemia hijacks the T-cell–prone PU.1 antisense promoter",

abstract = "The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of crucial transcription factors. One of the key master regulators in the hematopoietic systems is PU.1. Reduced levels of PU.1 are characteristic for human acute myeloid leukemia (AML) and are known to induce AML in mouse models. Here, we show that transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core-binding factor (CBF) fusions RUNX1-ETO and CBFβ-MYH11 in t(8;21) and inv(16) AML, respectively, activate the PU.1 antisense promoter that results in a shift from sense toward antisense transcription and myeloid differentiation blockade. In patients with CBF-AML, we found that an elevated antisense/sense transcript and promoter accessibility ratio represents a hallmark compared with normal karyotype AML or healthy CD34+ cells. Competitive interaction of an enhancer with the proximal or the antisense promoter forms a binary on/off switch for either myeloid or T-cell development. Leukemic CBF fusions thus use a physiological mechanism used by T cells to decrease sense transcription. Our study is the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. Hence, this disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.",

author = "{van der Kouwe}, E. and G. Heller and A. Czibere and Pulikkan, {J. A.} and C. Agreiter and Castilla, {L. H.} and R. Delwel and {Di Ruscio}, A. and Ebralidze, {A. K.} and M. Forte and F. Grebien and E. Heyes and L. Kazianka and J. Klinger and C. Kornauth and T. Le and K. Lind and Barbosa, {I. A.M.} and T. Pemovska and A. Pichler and Schmolke, {A. S.} and Schweicker, {C. M.} and H. Sill and Sperr, {W. R.} and A. Spittler and S. Surapally and Trinh, {B. Q.} and P. Valent and K. Vanura and Welner, {R. S.} and J. Zuber and Tenen, {D. G.} and Staber, {P. B.}",

note = "Funding Information: The authors acknowledge the Core Facilities of the Medical University of Vienna. The authors acknowledge the Biomedical Sequencing Facility, Center for Molecular Medicine (CeMM). A.D.R. was supported by grants from the National Institutes of Health (NIH), National Cancer Institute (R00CA188595), the Department of Defense (award number W81XWH-20-1-0518), Fondazione Cariplo N. 2016-0476, and the Giovanni Armenise-Harvard Foundation. A.K.E. was supported by the NIH, National Cancer Institute (R50 CA211304); P.V. was supported by the Austrian Science Fund (SFB grant F4704-B20). B.Q.T. is supported by the NIH, National Cancer Institute (K01CA222707). D.G.T. was supported by the NIH, National Cancer Institute (R35CA197697) and the National Heart, Lung, and Blood Institute (P01HL131477), and by the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award, and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.? P.B.S. received funding from the Austrian Science Fund (grant P27132-B20) and the Anniversary Fund of the Oesterreichische Nationalbank (grant P15936). Funding Information: A.D.R. was supported by grants from the National Institutes of Health (NIH), National Cancer Institute (R00CA188595), the Department of Defense (award number W81XWH-20-1-0518), Fondazione Cariplo N. 2016-0476, and the Giovanni Armenise-Harvard Foundation. A.K.E. was supported by the NIH, National Cancer Institute (R50 CA211304); P.V. was supported by the Austrian Science Fund (SFB grant F4704-B20). B.Q.T. is supported by the NIH, National Cancer Institute (K01CA222707). D.G.T. was supported by the NIH, National Cancer Institute (R35CA197697) and the National Heart, Lung, and Blood Institute (P01HL131477), and by the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award, and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.” P.B.S. received funding from the Austrian Science Fund (grant P27132-B20) and the Anniversary Fund of the Oesterreichische Nationalbank (grant P15936). Publisher Copyright: {\textcopyright} 2021 American Society of Hematology",

year = "2021",

month = oct,

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doi = "10.1182/blood.2020008971",

language = "English",

volume = "138",

pages = "1345--1358",

journal = "Blood",

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van der Kouwe, E, Heller, G, Czibere, A, Pulikkan, JA, Agreiter, C, Castilla, LH, Delwel, R, Di Ruscio, A, Ebralidze, AK, Forte, M, Grebien, F, Heyes, E, Kazianka, L, Klinger, J, Kornauth, C, Le, T, Lind, K, Barbosa, IAM, Pemovska, T, Pichler, A, Schmolke, AS, Schweicker, CM, Sill, H, Sperr, WR, Spittler, A, Surapally, S, Trinh, BQ, Valent, P, Vanura, K, Welner, RS, Zuber, J, Tenen, DG & Staber, PB 2021, 'Core-binding factor leukemia hijacks the T-cell–prone PU.1 antisense promoter', Blood, vol. 138, no. 15, pp. 1345-1358. https://doi.org/10.1182/blood.2020008971

TY - JOUR

T1 - Core-binding factor leukemia hijacks the T-cell–prone PU.1 antisense promoter

AU - van der Kouwe, E.

AU - Heller, G.

AU - Czibere, A.

AU - Pulikkan, J. A.

AU - Agreiter, C.

AU - Castilla, L. H.

AU - Delwel, R.

AU - Di Ruscio, A.

AU - Ebralidze, A. K.

AU - Forte, M.

AU - Grebien, F.

AU - Heyes, E.

AU - Kazianka, L.

AU - Klinger, J.

AU - Kornauth, C.

AU - Le, T.

AU - Lind, K.

AU - Barbosa, I. A.M.

AU - Pemovska, T.

AU - Pichler, A.

AU - Schmolke, A. S.

AU - Schweicker, C. M.

AU - Sill, H.

AU - Sperr, W. R.

AU - Spittler, A.

AU - Surapally, S.

AU - Trinh, B. Q.

AU - Valent, P.

AU - Vanura, K.

AU - Welner, R. S.

AU - Zuber, J.

AU - Tenen, D. G.

AU - Staber, P. B.

N1 - Funding Information: The authors acknowledge the Core Facilities of the Medical University of Vienna. The authors acknowledge the Biomedical Sequencing Facility, Center for Molecular Medicine (CeMM). A.D.R. was supported by grants from the National Institutes of Health (NIH), National Cancer Institute (R00CA188595), the Department of Defense (award number W81XWH-20-1-0518), Fondazione Cariplo N. 2016-0476, and the Giovanni Armenise-Harvard Foundation. A.K.E. was supported by the NIH, National Cancer Institute (R50 CA211304); P.V. was supported by the Austrian Science Fund (SFB grant F4704-B20). B.Q.T. is supported by the NIH, National Cancer Institute (K01CA222707). D.G.T. was supported by the NIH, National Cancer Institute (R35CA197697) and the National Heart, Lung, and Blood Institute (P01HL131477), and by the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award, and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.? P.B.S. received funding from the Austrian Science Fund (grant P27132-B20) and the Anniversary Fund of the Oesterreichische Nationalbank (grant P15936). Funding Information: A.D.R. was supported by grants from the National Institutes of Health (NIH), National Cancer Institute (R00CA188595), the Department of Defense (award number W81XWH-20-1-0518), Fondazione Cariplo N. 2016-0476, and the Giovanni Armenise-Harvard Foundation. A.K.E. was supported by the NIH, National Cancer Institute (R50 CA211304); P.V. was supported by the Austrian Science Fund (SFB grant F4704-B20). B.Q.T. is supported by the NIH, National Cancer Institute (K01CA222707). D.G.T. was supported by the NIH, National Cancer Institute (R35CA197697) and the National Heart, Lung, and Blood Institute (P01HL131477), and by the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award, and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.” P.B.S. received funding from the Austrian Science Fund (grant P27132-B20) and the Anniversary Fund of the Oesterreichische Nationalbank (grant P15936). Publisher Copyright: © 2021 American Society of Hematology

PY - 2021/10/14

Y1 - 2021/10/14

N2 - The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of crucial transcription factors. One of the key master regulators in the hematopoietic systems is PU.1. Reduced levels of PU.1 are characteristic for human acute myeloid leukemia (AML) and are known to induce AML in mouse models. Here, we show that transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core-binding factor (CBF) fusions RUNX1-ETO and CBFβ-MYH11 in t(8;21) and inv(16) AML, respectively, activate the PU.1 antisense promoter that results in a shift from sense toward antisense transcription and myeloid differentiation blockade. In patients with CBF-AML, we found that an elevated antisense/sense transcript and promoter accessibility ratio represents a hallmark compared with normal karyotype AML or healthy CD34+ cells. Competitive interaction of an enhancer with the proximal or the antisense promoter forms a binary on/off switch for either myeloid or T-cell development. Leukemic CBF fusions thus use a physiological mechanism used by T cells to decrease sense transcription. Our study is the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. Hence, this disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.

AB - The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of crucial transcription factors. One of the key master regulators in the hematopoietic systems is PU.1. Reduced levels of PU.1 are characteristic for human acute myeloid leukemia (AML) and are known to induce AML in mouse models. Here, we show that transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core-binding factor (CBF) fusions RUNX1-ETO and CBFβ-MYH11 in t(8;21) and inv(16) AML, respectively, activate the PU.1 antisense promoter that results in a shift from sense toward antisense transcription and myeloid differentiation blockade. In patients with CBF-AML, we found that an elevated antisense/sense transcript and promoter accessibility ratio represents a hallmark compared with normal karyotype AML or healthy CD34+ cells. Competitive interaction of an enhancer with the proximal or the antisense promoter forms a binary on/off switch for either myeloid or T-cell development. Leukemic CBF fusions thus use a physiological mechanism used by T cells to decrease sense transcription. Our study is the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. Hence, this disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.

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U2 - 10.1182/blood.2020008971

DO - 10.1182/blood.2020008971

M3 - Article

C2 - 34010414

AN - SCOPUS:85112289640

SN - 0006-4971

VL - 138

SP - 1345

EP - 1358

JO - Blood

JF - Blood

IS - 15

ER -

Core-binding factor leukemia hijacks the T-cell–prone PU.1 antisense promoter

Abstract

Bibliographical note

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