Cooperative Enhancer Activation by TLX1 and STAT5 Drives Development of NUP214-ABL1/TLX1-Positive T Cell Acute Lymphoblastic Leukemia.
Cooperative Enhancer Activation by TLX1 and STAT5 Drives Development of NUP214-ABL1/TLX1-Positive T Cell Acute Lymphoblastic Leukemia.
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DOI：
10.1016/j.ccell.2018.07.007
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发表时间：
2018-08-13
期刊：
影响因子：
50.3
通讯作者：
Cools J
中科院分区：
文献类型：
--
作者：
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
NUP 214-ABL 1融合体是一种组成型激活的酪氨酸激酶，与T细胞急性淋巴细胞白血病（T-ALL）中TLX 1和TLX 3转录因子的过表达显着相关。在这里，我们使用转基因小鼠模型和人T-ALL细胞显示NUP 214-ABL 1与TLX 1合作驱动T-ALL发展。使用整合的ChIP测序，ATAC测序和RNA测序数据，我们证明了TLX 1和STAT 5，NUP 214-ABL 1的下游效应子，共结合平衡的增强子区域，并协同激活关键原癌基因如MYC和BCL 2的表达。通过BET抑制剂治疗抑制STAT 5、下调TLX 1或MYC或干扰增强子功能，导致靶基因表达减少并诱导白血病细胞死亡。TLX 1和STAT 5信号传导在T-ALL的发展中协同作用TLX 1和STAT 5共结合并激活致癌增强子前馈环导致MYC激活并募集到TLX 1/STAT 5增强子ABL 1抑制剂和BET/BCL 2抑制剂之间的协同作用改善了治疗反应Vanden Bempt et al.显示NUP 214-ABL 1与TLX 1协同驱动T细胞急性淋巴细胞白血病（T-ALL）发展，且NUP 214-ABL 1下游效应物STAT 5和TLX 1协同激活MYC和BCL 2的表达。抑制STAT 5、TLX 1、MYC或BCL 2可诱导T-ALL细胞死亡。
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. TLX1 and STAT5 signaling cooperate in the development of T-ALL TLX1 and STAT5 co-bind and activate oncogenic enhancers A feedforward loop leads to MYC activation and recruitment to TLX1/STAT5 enhancers Synergy between ABL1 inhibitors and BET/BCL2 inhibitors improves therapy response Vanden Bempt et al. show that NUP214-ABL1 cooperates with TLX1 to drive T cell acute lymphoblastic leukemia (T-ALL) development and that STAT5, the downstream effector of NUP214-ABL1, and TLX1 cooperatively activate the expression of MYC and BCL2. Inhibition of STAT5, TLX1, MYC, or BCL2 induces T-ALL cell death.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
4.8
作者：
Ariyoshi, K;Nosaka, T;Kitamura, T
通讯作者：
Kitamura, T
影响因子：
20.3
作者：
Burmeister, Thomas;Gokbuget, Nicola;Schwartz, Stefan
通讯作者：
Schwartz, Stefan
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
50.3
作者：
Dadi, Saida;Le Noir, Sandrine;Asnafi, Vahid
通讯作者：
Asnafi, Vahid