Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation

Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma

“…[22][23][24] ROR1 mAb 2A2 was active in blocking Wnt5a binding to ROR1 and its downstream signaling in CLL. 30,31 We observed that ROR1 2A2 was effective when used at similar concentrations as other ROR1 mAbs (5-10 mg/mL) 19,23 in ROR1 Figure 2C-D). Moreover, ROR1 2A2 cytotoxicity in Jeko-1 and Mino cells could be partially Hyper-CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; ND, not determined; R-Benda, rituximab and bendamustine; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-Fludarabine, rituximab and fludarabine.…”

“…In CLL, Wnt5a-ROR1 binding resulted in Rho GTPase activation and leukemia cell proliferation, 19 although it is not known whether NF-kB signaling is also activated downstream of RhoA/Rac1. Recombinant Wnt5a treatment of MCL cells resulted in increased nuclear levels of NF-kB p65, indicating that Wnt5a activates the NF-kB p65 pathway in MCL models presumably via ROR1 because ROR1 downregulation resulted in decreased Wnt5a levels.…”

“…The Wnt5a-ROR1/ROR2 pathway has been functionally linked to cell proliferation and survival in CLL, 19 therefore we assessed the expression levels of ROR1, ROR2, and Wnt5a in MCL cell lines and primary samples by immunoblotting, flow cytometry, and transcriptome and gene expression analysis. We observed variable expression of ROR1 in MCL cell lines and primary cells (Figure 1A-B; Table 1; supplemental Figure 1A-B).…”

“…[16][17][18] Wnt5a binding to ROR1 induces ROR1/ROR2 heterodimerization and subsequent engagement of guanine exchange factor intracellular signaling, resulting in leukemia cell survival and proliferation via activation of Rho GTPases in CLL cells. 19 Furthermore, high ROR1 levels on B-ALL or CLL cells can sustain prosurvival signaling through activation of MEK/ERK and AKT pathways, whereas targeting ROR1 expression efficiently induced apoptosis in malignant cells, suggesting a critical role for this molecule in maintaining cancer cell survival. [20][21][22][23][24] ROR1 monoclonal antibody (mAb) cirmtuzumab has shown excellent preclinical efficacy in directly inducing apoptosis in ROR1…”

Mass spectrometry-based identification of a naturally presented receptor tyrosine kinase-like orphan receptor 1-derived epitope recognized by CD8 + cytotoxic T cells

“…Thus, Wnt5a induced the formation of ROR1/ROR2 heterooligomers, which augmented the proliferation and migration of CLL cells. 8 In addition, a higher expression of ROR1 on CLL cells was associated with a significantly shorter overall survival of CLL patients, indicating that ROR1 may enhance disease progression. 9 Due to the expression profile and important role in CLL pathogenesis, antibodies and CAR-engi- Analyzing the NIH:OVCAR3 cell line we were able to identify the ROR1 peptide only when applying the parallel reaction monitoring method.…”