Maintenance and pharmacologic targeting of ROR1 protein levels via UHRF1 in t(1;19) pre-B-ALL.
Maintenance and pharmacologic targeting of ROR1 protein levels via UHRF1 in t(1;19) pre-B-ALL.
复制标题
DOI：
10.1038/s41388-018-0299-8
复制
发表时间：
2018-09
期刊：
影响因子：
8
通讯作者：
Tyner JW
中科院分区：
文献类型：
--
作者：
Chow M;Gao L;MacManiman JD;Bicocca VT;Chang BH;Alumkal JJ;Tyner JW
跨膜伪激酶ROR1的表达是t(1;19)-前b细胞急性淋巴细胞白血病（t（1;19）前b - all）、慢性淋巴细胞白血病和许多实体肿瘤存活所必需的。然而，由于ROR1激酶缺乏活性，用小分子靶向ROR1一直具有挑战性。为了鉴定调节ROR1表达的基因，从而可能作为替代药物靶点，我们采用了siRNA筛选方法，并确定表观遗传调节剂和E3泛素连接酶UHRF1以ROR1依赖的方式对t(1;19) pre-B-ALL细胞活力是必需的。在UHRF1沉默后，ROR1蛋白减少而不改变ROR1 mRNA，异位表达UHRF1足以增加ROR1水平。此外，蛋白酶体抑制可以挽救UHRF1沉默后ROR1蛋白的丢失，这表明蛋白酶体在UHRF1-ROR1轴中发挥作用。最后，我们发现ror1阳性细胞对uhrf1靶向药物萘撒林的敏感性是ror1阴性细胞的两倍，并且细胞凋亡增加。萘萨苷引起UHRF1和ROR1的表达降低，与单独使用任何一种抑制剂相比，萘萨苷与前b细胞受体信号传导抑制剂联合使用可进一步降低细胞存活率。因此，我们的工作揭示了UHRF1稳定ROR1的机制，提示了在t(1;19) pre-B-ALL和其他恶性肿瘤中抑制ROR1的潜在靶向策略。
Expression of the transmembrane pseudokinase ROR1 is required for survival of t(1;19)-pre-B-cell acute lymphoblastic leukemia (t(1;19) pre-B-ALL), chronic lymphocytic leukemia, and many solid tumors. However, targeting ROR1 with small-molecules has been challenging due to the absence of ROR1 kinase activity. To identify genes that regulate ROR1 expression and may, therefore, serve as surrogate drug targets, we employed an siRNA screening approach and determined that the epigenetic regulator and E3 ubiquitin ligase, UHRF1, is required for t(1;19) pre-B-ALL cell viability in a ROR1-dependent manner. Upon UHRF1 silencing, ROR1 protein is reduced without altering ROR1 mRNA, and ectopically expressed UHRF1 is sufficient to increase ROR1 levels. Additionally, proteasome inhibition rescues loss of ROR1 protein after UHRF1 silencing, suggesting a role for the proteasome in the UHRF1-ROR1 axis. Finally, we show that ROR1-positive cells are twice as sensitive to the UHRF1-targeting drug, naphthazarin, and undergo increased apoptosis compared to ROR1-negative cells. Naphthazarin elicits reduced expression of UHRF1 and ROR1, and combination of naphthazarin with inhibitors of pre-B cell receptor signaling results in further reduction of cell survival compared with either inhibitor alone. Therefore, our work reveals a mechanism by which UHRF1 stabilizes ROR1, suggesting a potential targeting strategy to inhibit ROR1 in t(1;19) pre-B-ALL and other malignancies.
登录
查看更多内容
UHRF1依赖性调节癌症中肿瘤基因的信号通路。
DOI：
10.1186/s13046-016-0453-5
发表时间：
2016-11-14
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Alhosin M;Omran Z;Zamzami MA;Al-Malki AL;Choudhry H;Mousli M;Bronner C
通讯作者：
Bronner C
影响因子：
20.3
作者：
Hudecek, Michael;Schmitt, Thomas M.;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
影响因子：
5.3
作者：
Baskar S;Wiestner A;Wilson WH;Pastan I;Rader C
通讯作者：
Rader C
DOI：
10.1073/pnas.0712148105
发表时间：
2008-02-26
影响因子：
11.1
作者：
Fukuda, Tetsuya;Chen, Liguang;Kipps, Thomas J.
通讯作者：
Kipps, Thomas J.
影响因子：
7.2
作者：
Acharya, Bipul R.;Bhattacharyya, Surela;Chakrabarti, Gopal
通讯作者：
Chakrabarti, Gopal