Department of Molecular, Cell and Cancer Biology
Amino Acids, Peptides, and Proteins | Cancer Biology | Neoplasms | Nucleic Acids, Nucleotides, and Nucleosides
The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of the hematopoietic master regulator PU.11–4. PU.1 gene expression is regulated through enhancer-promoter interactions within a topologically associated domain (TAD)5,6. PU.1 levels increase during myeloid differentiation while failure to do so results in myeloid leukemia7. In contrast, T-cell differentiation requires PU.1 to be completely switched off8–10. Little is known about the precise mechanisms of PU.1 repression, physiological as in T-cell differentiation, or pathological as in leukemia. Here we demonstrate that the down-regulation of PU.1 mRNA is a dynamic process involving an alternative promoter11 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) acute myeloid leukemia (AML)12, activate the PU.1 antisense promoter, thus shifting from sense towards antisense transcription and blocking myeloid differentiation. In patients with CBF-AML, we found that an elevated antisense/sense ratio represents a hallmark compared to normal karyotype AML or healthy CD34+ cells. Competitive interaction of the enhancer with the proximal or the antisense promoter are at the heart of differential PU.1 expression during myeloid and T-cell development. Leukemic CBF fusions thus utilize a physiologic mechanism employed by T-cells to decrease sense PU.1 transcription. Our results identify the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. This novel basic disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.
cancer biology, core binding factor leukemia, antisense promoter, cell differentiation
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
DOI of Published Version
bioRxiv 2020.05.29.120857; doi: 10.1101/2020.05.29.120857. Link to preprint on bioRxiv service
van der Kouwe E, Castilla LH, Tenen DG, Staber PB. (2020). Core binding factor leukemia hijacks T-cell prone PU.1 antisense promoter [preprint]. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/2020.05.29.120857. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1707
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.