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

Research output: Contribution to journalArticleAcademicpeer-review

8 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 languageEnglish
Pages (from-to)1345-1358
Number of pages14
JournalBlood
Volume138
Issue number15
DOIs
Publication statusPublished - 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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