NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia.
NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia.
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DOI：
10.1084/jem.20100745
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发表时间：
2010-09-27
期刊：
影响因子：
--
通讯作者：
Roméo PH
中科院分区：
文献类型：
--
作者：
Kusy S;Gerby B;Goardon N;Gault N;Ferri F;Gérard D;Armstrong F;Ballerini P;Cayuela JM;Baruchel A;Pflumio F;Roméo PH
TAL 1（也称为SCL）在>40%的人T细胞急性淋巴细胞白血病（T-ALL）中表达。TAL 1编码一种碱性螺旋-环-螺旋转录因子，可在T细胞白血病发生过程中干扰E2 A和HEB的转录活性;然而，由TAL 1直接激活的致癌途径尚不清楚。在这项研究中，我们表明，在人类TAL 1表达T-ALL细胞系，TAL 1直接激活NKX3.1，前列腺干细胞维持所需的肿瘤抑制基因。在人T-ALL细胞系中，NKX3.1基因激活由TAL 1-LMO-Ldb 1复合物介导，该复合物由结合至NKX3.1基因启动子调控序列的加塔-3募集。TAL 1诱导的NKX3.1激活与NKX3.1基因启动子上的HP 1-α（异染色质蛋白1 α）结合和染色质开放的抑制有关。NKX3.1是T-ALL增殖所必需的，可以部分恢复TAL 1敲减细胞的增殖，并直接调节miR-17-92。在原代表达人TAL 1的白血病细胞中，NKX3.1基因的表达独立于Notch途径，其失活损害增殖。最后，TAL 1或NKX3.1敲低消除了人T-ALL细胞在小鼠中有效诱导白血病发展的能力。这些结果表明NKX3.1的肿瘤抑制或致癌活性取决于组织表达。
TAL1 (also known as SCL) is expressed in >40% of human T cell acute lymphoblastic leukemias (T-ALLs). TAL1 encodes a basic helix-loop-helix transcription factor that can interfere with the transcriptional activity of E2A and HEB during T cell leukemogenesis; however, the oncogenic pathways directly activated by TAL1 are not characterized. In this study, we show that, in human TAL1–expressing T-ALL cell lines, TAL1 directly activates NKX3.1, a tumor suppressor gene required for prostate stem cell maintenance. In human T-ALL cell lines, NKX3.1 gene activation is mediated by a TAL1–LMO–Ldb1 complex that is recruited by GATA-3 bound to an NKX3.1 gene promoter regulatory sequence. TAL1-induced NKX3.1 activation is associated with suppression of HP1-α (heterochromatin protein 1 α) binding and opening of chromatin on the NKX3.1 gene promoter. NKX3.1 is necessary for T-ALL proliferation, can partially restore proliferation in TAL1 knockdown cells, and directly regulates miR-17-92. In primary human TAL1-expressing leukemic cells, the NKX3.1 gene is expressed independently of the Notch pathway, and its inactivation impairs proliferation. Finally, TAL1 or NKX3.1 knockdown abrogates the ability of human T-ALL cells to efficiently induce leukemia development in mice. These results suggest that tumor suppressor or oncogenic activity of NKX3.1 depends on tissue expression.
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影响因子：
16
作者：
Fujiwara T;O'Geen H;Keles S;Blahnik K;Linnemann AK;Kang YA;Choi K;Farnham PJ;Bresnick EH
通讯作者：
Bresnick EH
影响因子：
64.5
作者：
BENEZRA, R;DAVIS, RL;WEINTRAUB, H
通讯作者：
WEINTRAUB, H
影响因子：
20.3
作者：
Lécuyer, E;Herblot, S;Hoang, T
通讯作者：
Hoang, T
影响因子：
4.4
作者：
He, WW;Sciavolino, PJ;Carter, KC
通讯作者：
Carter, KC
DOI：
10.1073/pnas.91.8.3181
发表时间：
1994-04-12
影响因子：
11.1
作者：
HSU, HL;WADMAN, I;BAER, R
通讯作者：
BAER, R