| Autor: |
E. van der Kouwe, G. Heller, A. Czibere, L.H. Castilla, R. Delwel, A. Di Ruscio, A.K. Ebralidze, M. Forte, L. Kazianka, C. Kornauth, T. Le, K. Lind, I.A. Monteiro Barbosa, A. Pichler, J.A. Pulikkan, A-S Schmolke, H. Sill, W.R. Sperr, A. Spittler, B. Q. Trinh, P. Valent, K. Vanura, R.S. Welner, J. Zuber, D.G. Tenen, P.B. Staber |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.05.29.120857 |
| Popis: |
Summary paragraphThe 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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