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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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Main Authors: Bempt, Marlies vanden (Author) , Demeyer, Sofie (Author) , Broux, Michaël (Author) , De Bie, Jolien (Author) , Bornschein, Simon (Author) , Mentens, Nicole (Author) , Vandepoel, Roel (Author) , Geerdens, Ellen (Author) , Radaelli, Enrico (Author) , Bornhauser, Beat C. (Author) , Kulozik, Andreas (Author) , Meijerink, Jules P. (Author) , Bourquin, Jean-Pierre (Author) , de Bock, Charles E. (Author) , Cools, Jan (Author)
Format: Article (Journal)
Language:English
Published: 13 August 2018
In: Cancer cell
Year: 2018, Volume: 34, Issue: 2, Pages: 271-285.e7
ISSN:1878-3686
DOI:10.1016/j.ccell.2018.07.007
Online Access: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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Author Notes: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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Summary: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.
Item Description:Gesehen am 24.03.2020
Physical Description:Online Resource
ISSN:1878-3686
DOI:10.1016/j.ccell.2018.07.007

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