Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, Cell Biology, BROMODOMAIN INHIBITOR OTX015, AMPLIFIED EPISOMES, DOSE-ESCALATION, READ ALIGNMENT, CHIP-SEQ, MYC, FUSION, NUP214-ABL1, MUTATIONS, ABL1, cancer, cooperation, leukemia, mouse model, oncogenes, signaling, transcriptional regulation, Animals, Enhancer Elements, Genetic, Gene Fusion, Homeodomain Proteins, Humans, Mice, Nuclear Pore Complex Proteins, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-abl, Proto-Oncogene Proteins c-myc, STAT5 Transcription Factor, DEEP-SEQUENCING DATA, SUPER-ENHANCERS, GENE-EXPRESSION, TRANSFORMATION, 1109 Neurosciences, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3101 Biochemistry and cell biology, 3211 Oncology and carcinogenesis

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.