Cooperative enhancer activation by TLX1 and STAT5 drives development of NUP214-ABL1/TLX1-positive T cell acute lymphoblastic leukemia
The NUP214-ABL1 fusion is a constitutively activated tyrosine kinase that is significantly associated with overexpression of the TLX1 and TLX3 transcription factors in T cell acute lymphoblastic leukemia (T-ALL). Here we show that NUP214-ABL1 cooperates with TLX1 in driving T-ALL development using a...
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| Hauptverfasser: | , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
13 August 2018
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| In: |
Cancer cell
Year: 2018, Jahrgang: 34, Heft: 2, Pages: 271-285.e7 |
| ISSN: | 1878-3686 |
| DOI: | 10.1016/j.ccell.2018.07.007 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ccell.2018.07.007 Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S1535610818303131 
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| Verfasserangaben: | Marlies Vanden Bempt, Sofie Demeyer, Michaël Broux, Jolien De Bie, Simon Bornschein, Nicole Mentens, Roel Vandepoel, Ellen Geerdens, Enrico Radaelli, Beat C. Bornhauser, Andreas E. Kulozik, Jules P. Meijerink, Jean-Pierre Bourquin, Charles E. de Bock, Jan Cools |
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| 245 | 1 | 0 | |a Cooperative enhancer activation by TLX1 and STAT5 drives development of NUP214-ABL1/TLX1-positive T cell acute lymphoblastic leukemia |c Marlies Vanden Bempt, Sofie Demeyer, Michaël Broux, Jolien De Bie, Simon Bornschein, Nicole Mentens, Roel Vandepoel, Ellen Geerdens, Enrico Radaelli, Beat C. Bornhauser, Andreas E. Kulozik, Jules P. Meijerink, Jean-Pierre Bourquin, Charles E. de Bock, Jan Cools |
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| 520 | |a The NUP214-ABL1 fusion is a constitutively activated tyrosine kinase that is significantly associated with overexpression of the TLX1 and TLX3 transcription factors in T cell acute lymphoblastic leukemia (T-ALL). Here we show that NUP214-ABL1 cooperates with TLX1 in driving T-ALL development using a transgenic mouse model and human T-ALL cells. Using integrated ChIP-sequencing, ATAC-sequencing, and RNA-sequencing data, we demonstrate that TLX1 and STAT5, the downstream effector of NUP214-ABL1, co-bind poised enhancer regions, and cooperatively activate the expression of key proto-oncogenes such as MYC and BCL2. Inhibition of STAT5, downregulation of TLX1 or MYC, or interference with enhancer function through BET-inhibitor treatment leads to reduction of target gene expression and induction of leukemia cell death. | ||
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