August 13, 2018
synergy between the different compounds, ALL-SIL, mouse leukemic cells or patient-derived xenograft cells were seeded into 96-well plates and the compounds were added in a randomized fashion using a D300e digital dispenser (Tecan). The DMSO concentration was normalized. Cell proliferation was measured after 48 hours using the ATPlite luminescence system (PerkinElmer) using a Victor multilabel pla;synergy between the different compounds, ALL-SIL, mouse leukemic cells or patient-derived xenograft cells were seeded into 96-well plates and the compounds were added in a randomized fashion using a D300e digital dispenser (Tecan). The DMSO concentration was normalized. Cell proliferation was measured after 48 hours using the ATPlite luminescence system (PerkinElmer) using a Victor multilabel pla
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. Copyright Š 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
Vanden Bempt, M; Demeyer, S; Broux, M; De Bie, J; Bornschein, S; Mentens, N; Vandepoel, R; Geerdens, E; Radaelli, E; Bornhauser, BC; Kulozik, AE; Meijerink, JP; Bourquin, JP; de Bock, CE; Cools, J;
Journal: Cancer Cell Pages: 271-285.e7