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Cirmtuzumab Blocks Wnt5a/ROR1-Stimulation Of NF-κB To Repress Autocrine STAT3-Activation In Chronic Lymphocytic Leukemia

Yun Chen, Liguang Chen, Jian Yu, Emanuela M. Ghia, Michael Y. Choi, Ling Zhang, Suping Zhang, Elsa Sanchez-Lopez, George F. Widhopf II, Karen Messer, Laura Z. Rassenti, Catriona Jamieson and Thomas J. Kipps

Key Points

  • Nurselike cells express Wnt5a To Induce ROR1-dependent stimulation of NF-kB, which leads to autocrine IL-6 STAT3-activation in CLL cells.

  • Cirmtuzumab inhibits Wnt5a-induced, ROR1-dependent stimulation of NF-κB and thereby represses autocrine IL-6 of STAT3-activation in CLL

Abstract

Co-culture of Nurse-like Cells (NLC) 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 mAb, cirmtuzumab. Time-course studies revealed Wnt5a could induce activation ofNF-κB within 30 minutes, but required over 3 hours to induce pSTAT3. Cultureof isolated CLL cells for 24 hours revealed Wnt5a induced expression of IL-6, IL-8, CCL2, CCL3, CCL4, and CXCL1, which in turn could induce pSTAT3 in unstimulated CLL cells within 30 minutes. We found Wnt5a could induce CLL-cell expression of NF-κB target genes, including IL-6, and that this effect could be blocked by cirmtuzumab or drugs that inhibit NF-κB. Examination of CLL cells and plasma collected from patients treated with cirmtuzumab revealed reduced levels of phosphorylated p65 and diminished expression of NF-κB- and STAT3-target genes in CLL cells, and 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-κB, 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-κB and STAT3 in patients with CLL.

  • Submitted January 31, 2019.
  • Revision received August 12, 2019.
  • Accepted June 21, 2019.