Cooperative Enhancer Activation by TLX1 and STAT5 Drives Development of NUP214-ABL1/TLX1-Positive T Cell Acute Lymphoblastic Leukemia

  • Cancer Cell. 2018 Aug 13;34(2):271-285.e7. doi: 10.1016/j.ccell.2018.07.007.
Marlies Vanden Bempt  1 ,  Sofie Demeyer  1 ,  Michaël Broux  1 ,  Jolien De Bie  1 ,  Simon Bornschein  1 ,  Nicole Mentens  1 ,  Roel Vandepoel  1 ,  Ellen Geerdens  1 ,  Enrico Radaelli  2 ,  Beat C Bornhauser  3 ,  Andreas E Kulozik  4 ,  Jules P Meijerink  5 ,  Jean-Pierre Bourquin  3 ,  Charles E de Bock  6 ,  Jan Cools  7
Affiliations
  • 1. KU Leuven Center for Human Genetics, KU Leuven, Leuven, Belgium; VIB Center for Cancer Biology, VIB, Leuven, Belgium.
  • 2. KU Leuven Center for Human Genetics, KU Leuven, Leuven, Belgium.
  • 3. Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
  • 4. Department of Pediatric Hematology and Oncology, Heidelberg University Children's Hospital, Heidelberg, Germany; Hopp Children's Cancer Center at the NCT Heidelberg, Heidelberg, Germany.
  • 5. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • 6. KU Leuven Center for Human Genetics, KU Leuven, Leuven, Belgium; VIB Center for Cancer Biology, VIB, Leuven, Belgium. Electronic address: [email protected].
  • 7. KU Leuven Center for Human Genetics, KU Leuven, Leuven, Belgium; VIB Center for Cancer Biology, VIB, Leuven, Belgium. Electronic address: [email protected].
PMID: 30107177 DOI: 10.1016/j.ccell.2018.07.007
Abstract

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.

Keywords
cancer; cooperation; leukemia; mouse model; oncogenes; signaling; transcriptional regulation.
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