Cirmtuzumab blocks Wnt5a/ROR1 stimulation of NF-{kappa}B to repress autocrine STAT3 activation in chronic lymphocytic leukemia

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-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-B target genes, including IL-6, and that this effect could be blocked by cirmtuzumab or drugs that inhibit NF-B. Examination of CLL cells and plasma collected from patients treated with cirmtuzumab revealed reduced levels of phosphorylated p65 and diminished expression of NF-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-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-B and STAT3 in patients with CLL.

Source: Blood - September 25, 2019 Category: Hematology Authors: Chen, Y., Chen, L., Yu, J., Ghia, E. M., Choi, M. Y., Zhang, L., Zhang, S., Sanchez-Lopez, E., Widhopf, G. F., Messer, K., Rassenti, L. Z., Jamieson, C., Kipps, T. J. Tags: Lymphoid Neoplasia Source Type: research