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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: Bempt, Marlies vanden (VerfasserIn) , Demeyer, Sofie (VerfasserIn) , Broux, Michaël (VerfasserIn) , De Bie, Jolien (VerfasserIn) , Bornschein, Simon (VerfasserIn) , Mentens, Nicole (VerfasserIn) , Vandepoel, Roel (VerfasserIn) , Geerdens, Ellen (VerfasserIn) , Radaelli, Enrico (VerfasserIn) , Bornhauser, Beat C. (VerfasserIn) , Kulozik, Andreas (VerfasserIn) , Meijerink, Jules P. (VerfasserIn) , Bourquin, Jean-Pierre (VerfasserIn) , de Bock, Charles E. (VerfasserIn) , Cools, Jan (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 13 August 2018
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
Volltext
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
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 24.03.2020
Beschreibung:Online Resource
ISSN:1878-3686
DOI:10.1016/j.ccell.2018.07.007

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