Cooperation between TLX1 and the NUP214-ABL1/STAT5 signaling in T-cell acute lymphoblastic leukemia

The NUP214-ABL1 fusion is a constitutively activated tyrosine kinase that is significantly associated with overexpression of the TLX1 or TLX3 transcription factors in T-cell acute lymphoblastic (T-ALL). Here we show that NUP214-ABL1 kinase cooperates with TLX1 in driving T-ALL development using a transgenic mouse model. Using ChIP-seq and ATAC-seq, we show that TLX1 and STAT5, the downstream effector of NUP214-ABL1, selectively increase the accessibility of enhancer regions, and cooperatively activate the expression of key proto-oncogenes such as MYC and BCL2. Moreover, MYC is also part of the TLX1/STAT5 complex and inhibition of both MYC and STAT5 leads to reduction of target gene expression. RNA-sequencing of different conditions: wild type, NUP214-ABL1 +, TLX1 +, NUP214-ABL1+TLX1 +, NUP214-ABL1+TLX3 +. Transgenic mouse samples and ALL-SIL cell line. Xenografts of patient samples. Before and after treatment with Imatinib. ChIPmentation sequencing with different antibodies: STAT5, TLX1, H3K4me3, H3K27ac, p300 and BRD4. Transgenic mouse with NUP214-ABL1+TLX1 +. ATAC-sequencing for different conditions in mouse: wild type, NUP214-ABL1 +, TLX1 +, NUP214-ABL1+TLX1 +.