Wnt5a enhances proliferation of chronic lymphocytic leukemia and ERK1/2 phosphorylation via a ROR1/DOCK2-dependent mechanism.
Wnt5a enhances proliferation of chronic lymphocytic leukemia and ERK1/2 phosphorylation via a ROR1/DOCK2-dependent mechanism.
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Wnt 5a通过ROR 1/DOCK 2依赖性机制增强慢性淋巴细胞白血病的增殖和ERK 1/2磷酸化
DOI：
10.1038/s41375-020-01055-7
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发表时间：
2021-06
期刊：
影响因子：
11.4
通讯作者：
Kipps TJ
中科院分区：
文献类型：
--
作者：
Hasan MK;Ghia EM;Rassenti LZ;Widhopf GF 2nd;Kipps TJ
慢性淋巴细胞性白血病（CLL）患者血浆中Wnt 5a水平较高，可诱导ERK 1/2磷酸化并增强CLL细胞增殖。这种作用可以通过使用ERK 1/2抑制剂、ERK 1/2特异性siRNA或cirmtuzumab（一种抗ROR 1 mAb）治疗来抑制。CLL衍生系MEC 1表达Wnt 5a，但不表达ROR 1。转染以表达ROR 1的MEC 1细胞（MEC 1-ROR 1）具有比亲本MEC 1、或用ROR 1 ΔPRD（一种缺乏胞质富含脯氨酸结构域（PRD）的截短ROR 1）转染的MEC 1、或ROR 1 P808 A（一种在808处具有P→A取代的突变ROR 1）转染的MEC 1更高水平的磷酸化ERK 1/2，在用Wnt 5a刺激后，其是与Rac特异性鸟嘌呤核苷酸交换因子DOCK 2复合所需的。我们用siRNA沉默DOCK 2，发现这抑制了Wnt 5a诱导MEC 1-ROR 1或CLL细胞中ERK 1/2磷酸化的能力。表达ROR 1的CLL细胞比缺乏ROR 1的CLL细胞具有更高水平的磷酸化ERK 1/2或DOCK 2。虽然我们发现伊曲替尼可以抑制B细胞受体连接诱导的ERK 1/2和DOCK 2的磷酸化，但我们发现这种药物不能抑制Wnt 5a诱导的ROR 1依赖性ERK 1/2或DOCK 2的磷酸化。这项研究表明，Wnt 5a可以诱导ERK 1/2的激活，并通过ROR 1/DOCK 2依赖性途径增强CLL细胞增殖，而不依赖于BTK。
Patients with chronic lymphocytic leukemia (CLL) have high plasma-levels of Wnt5a, which can induce phosphorylation of ERK1/2 and enhance CLL-cell proliferation. Such effects could be inhibited by treatment with an ERK1/2 inhibitor, ERK1/2-specific siRNA, or cirmtuzumab, an anti-ROR1 mAb. The CLL-derived line, MEC1, expresses Wnt5a, but not ROR1. MEC1 cells transfected to express ROR1 (MEC1-ROR1) had higher levels of phosphorylated ERK1/2 than parental MEC1, or MEC1 transfected with ROR1ΔPRD, a truncated ROR1 lacking the cytoplasmic proline-rich domain (PRD), or ROR1P808A a mutant ROR1 with a P→A substitution at 808, which is required for complexing with the Rac-specific-guanine-nucleotide-exchange factor DOCK2 upon stimulation with Wnt5a. We silenced DOCK2 with siRNA and found this repressed the capacity of Wnt5a to induce ERK1/2 phosphorylation in MEC1-ROR1 or CLL cells. CLL cells that expressed ROR1 had higher levels of phosphorylated ERK1/2 or DOCK2 than CLL cells lacking ROR1. Although we found ibrutinib could inhibit the phosphorylation of ERK1/2 and DOCK2 induced by B-cell-receptor ligation, we found that this drug was unable to inhibit Wnt5a-induced, ROR1-dependent phosphorylation of ERK1/2 or DOCK2. This study demonstrates that Wnt5a can induce activation of ERK1/2 and enhance CLL-cell proliferation via a ROR1/DOCK2-dependent pathway independent of BTK.
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影响因子：
14.8
作者：
Chaikuad A;Tacconi EM;Zimmer J;Liang Y;Gray NS;Tarsounas M;Knapp S
通讯作者：
Knapp S
DOI：
10.1126/science.1170179
发表时间：
2009-04-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Nishikimi A;Fukuhara H;Su W;Hongu T;Takasuga S;Mihara H;Cao Q;Sanematsu F;Kanai M;Hasegawa H;Tanaka Y;Shibasaki M;Kanaho Y;Sasaki T;Frohman MA;Fukui Y
通讯作者：
Fukui Y
DOI：
10.1038/nrdp.2016.96
发表时间：
2017-01-19
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
Kipps TJ;Stevenson FK;Wu CJ;Croce CM;Packham G;Wierda WG;O'Brien S;Gribben J;Rai K
通讯作者：
Rai K
影响因子：
20.3
作者：
Apollonio, Benedetta;Scielzo, Cristina;Caligaris-Cappio, Federico
通讯作者：
Caligaris-Cappio, Federico
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.