Orphan receptor tyrosine kinases ROR1 and ROR2 in hematological malignancies

Abstract

The receptor tyrosine kinase ROR1 has been shown to be overexpressed in chronic lymphocytic leukemia (CLL). The aim of this study was to further characterize the expression of ROR1 and the other member of the ROR family, ROR2, in other lymphoid and myeloid malignancies. Normal white blood cells and reactive lymph nodes were negative for ROR1 and ROR2. A significantly high and uniform surface expression of ROR1 was found in CLL/hairy cell leukemia (HCL) compared to mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), myelomas, acute lymphoblastic leukemia (ALL) and myeloid leukemias (p = 0.02 to < 0.001). The lowest proportion of ROR1+ cells was seen in FL, whereas CLL, HCL and CML had significantly higher numbers of ROR1+ cells. Longitudinal follow-up of individual patients with CLL revealed that ROR1+ cells remained stable over time in non-progressive patients, but increased when the disease progressed (p < 0.05). Thus, a variable staining pattern of ROR1 ranging from very high (CLL, HCL) and high (CML) to intermediate (myeloma and DLBCL) or low (FL) was noted. ROR2 was not detected in hematological malignancies.

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

“…Evaluation of serial samples revealed that the expression levels of ROR1 did not vary substantially over time, as noted in a prior study. 19 However, this earlier study also noted an increase in the frequency of ROR1 Pos CLL cells had enhanced activation of AKT signaling pathways, we found that ratios of activated AKT (phosphorylated AKT) to total AKT in ROR1 Pos CLL were higher than those of ROR1 Neg CLL samples. Such differences were comparable to those noted between the ROR1 Pos leukemia of ROR1xTCL1 transgenic mice relative to the ROR1 Neg leukemia that develops in otherwise syngeneic TCL1 transgenic mice.…”

Expression of ROR1, pAkt, and pCREB in gastric adenocarcinoma

“…Monoclonal antibodies to ROR1 and frizzled domain showing cytotoxicity have been demonstrated in cell lines. Inhibition of tyrosine kinase or immunotargeting of ROR1 molecule also could be prospective in the treatment of cancers [8,9]. In this study, we firstly revealed that ROR1 is highly expressed in gastric adenocarcinoma and ROR1 could be a possible target for gastric cancer therapy.…”

“…Although the expression of ROR1 is low in mature human tissues, some subsequent studies have revealed that ROR1 is expressed in cancer cells. In some blood malignancies including chronic lymphocytic leukemia, chronic myelogenous leukemia, and diffuse large B-cell lymphoma, expression of ROR1 was observed [8,9]. High expression of ROR1 is also observed in many solid malignancies such as colon, lung, pancreatic, prostate, and breast cancer tissues [10,11].…”

ROR1, an embryonic protein with an emerging role in cancer biology

“…This differential expression pattern, low ROR1 expression in adult tissue and high expression in cancer have led investigators to examine the functional advantage conferred to cancer by ROR1 expression and to explore the use of immune-based therapies against ROR1 for targeting cancer cells. (Baskar et al, 2008; Barna et al, 2011; Zhang et al, 2012a; Zhang et al, 2012b; Daneshmanesh et al, 2013)…”