Cirmtuzumab blocks Wnt5a/ROR1 stimulation of NF-κB to repress autocrine STAT3 activation in chronic lymphocytic leukemia
Cirmtuzumab blocks Wnt5a/ROR1 stimulation of NF-κB to repress autocrine STAT3 activation in chronic lymphocytic leukemia
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DOI：
10.1182/blood.2019001366
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发表时间：
2019-09-26
期刊：
影响因子：
20.3
通讯作者：
Kipps, Thomas J.
中科院分区：
文献类型：
--
作者：
Chen, Yun;Chen, Liguang;Kipps, Thomas J.
Nurse-like细胞（NLC）与慢性淋巴细胞白血病（CLL）细胞的共培养诱导了白血病细胞STAT 3（pSTAT 3）的磷酸化，这可以被抗Wnt 5a抗体或抗ROR 1单克隆抗体cirmtuzumab阻断。时程研究显示Wnt 5a可在30分钟内诱导NF-κ B活化，但需要超过3小时才能诱导pSTAT 3。将分离的CLL细胞培养24小时揭示了Wnt 5a诱导的白细胞介素6（IL-6）、IL-8、CCL 2、CCL 3、CCL 4和CXCL 1的表达，其进而可以在30分钟内在未刺激的CLL细胞中诱导pSTAT 3。我们发现Wnt 5a可以诱导CLL细胞表达NF-κ B靶基因，包括IL-6，并且这种作用可以被cirmtuzumab或抑制NF-κ B的药物阻断。对从用cirmtuzumab治疗的患者收集的CLL细胞和血浆的检查显示，在治疗后的样品中，CLL细胞中磷酸化p65的水平降低，NF-κ B和STAT 3靶基因的表达减少，以及IL-6的血浆水平降低。总的来说，这些研究表明Wnt 5a/ROR 1依赖性信号传导有助于NF-κ B B的CLL细胞活化，这反过来又导致自分泌IL-6诱导的pSTAT 3活化。因此，本研究表明，cirmtuzumab可抑制CLL患者中NF-κ B和STAT 3的白血病细胞活化。
Coculture of nurse-like cells (NLCs) with chronic lymphocytic leukemia (CLL) cells induced leukemia cell phosphorylation of STAT3 (pSTAT3), which could be blocked by anti-Wnt5a antibodies or the anti-ROR1 monoclonal antibody, cirmtuzumab. Time-course studies revealed Wnt5a could induce activation of NF-kappa B within 30 minutes, but required more than 3 hours to induce pSTAT3. Culture of isolated CLL cells for 24 hours revealed Wnt5a-induced expression of interleukin 6 (IL-6), IL-8, CCL2, CCL3, CCL4, and CXCL1, which in turn could induce pSTAT3 in unstimulated CLL cells within 30 minutes. We found that Wnt5a could induce CLL cell expression of NF-kappa B target genes, including IL-6, and that this effect could be blocked by cirmtuzumab or drugs that inhibit NF-kappa B. Examination of CLL cells and plasma collected from patients treated with cirmtuzumab revealed reduced levels of phosphorylated p65 and diminished expression of NF-kappa B and STAT3 target genes in CLL cells, as well as lower plasma levels of IL-6, in the samples after therapy. Collectively, these studies indicate that Wnt5a/ROR1-dependent signaling contributes to CLL cell activation of NF-kappa B, which in turn causes autocrine IL-6-induced activation of pSTAT3. As such, this study demonstrates that cirmtuzumab can inhibit leukemia cell activation of both NF-kappa B and STAT3 in patients with CLL.