High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia

Abstract

which we randomly assigned to a training or validation set of 797 or 771 cases, respectively. Using recursive partitioning, we defined a threshold for ROR1 surface expression that could segregate samples of the training set into ROR1-Hi vs ROR1-Lo subgroups that differed significantly in their median treatment-free survival (TFS). Using this threshold, we found that ROR1-Hi cases had a significantly shorter median TFS and overall survival than ROR1-Lo cases in the validation set. These data demonstrate that expression of ROR1 may promote leukemia-cell activation and survival and enhance disease progression in patients with CLL. (Blood. 2016;128(25):2931-2940

Chronic lymphocytic leukaemia

“…In addition, the elaboration of various WNT proteins by cells in the microenvironment can activate canonical and non-canonical WNT signalling pathways 92,93 . Activation of the tyrosine-kinase-like transmembrane receptor ROR1 by WNT5A can induce the activation of RAC1 and RHOA, and thereby enhance CLL cell proliferation and promote migration in response to chemokines 93 ; in part, for this reason, high-level CLL cell expression of ROR1 is associated with accelerated disease progression 94 . Finally, Notch signalling in response to Jagged, or Hedgehog signalling in response to Sonic Hedgehog or Desert Hedgehog, can provide pro-survival stimulation for at least a subset of patients with CLL, particularly those with trisomy 12 (REFS 95–97).…”

“…CLL cells also express CD200 (also known as OX-2 membrane glycoprotein), which can help to distinguish CLL from mantle cell lymphoma 109 . In addition, the CLL cells of >95% of patients express the onco-embryonic surface antigen ROR1 (REFS 94,110). …”

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

“…We found considerable heterogeneity in expression of ROR1 in MCL cell lines and primary samples as examined at the protein, mRNA, and gene-expression levels, indicating as previously observed that ROR1 is not uniformly expressed on malignant B cells. 34 Even in CLL, a B-cell leukemia with the highest ROR1 median expression among hematological cancers, Cui et al 20 were able to detect leukemic cells with very low or very high ROR1 expression. ROR1 ligand Wnt5a had a similar heterogeneous expression whereas ROR2 levels were almost negligible.…”

“…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

“…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. Here the peptide was identified with an oxidized methionine, which is indicated by a small 'm' (NPRYPNYmF).…”