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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2018 Aug 15

PMID 30107177

Citations 32

Authors

Marlies Vanden Bempt

Sofie Demeyer

Michael 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

Affiliations

Soon will be listed here.

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.

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