Expression of COBLL1 encoding novel ROR1 binding partner is robust predictor of survival in chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia is a disease with up-regulated expression of the transmembrane tyrosine-protein kinase ROR1, a member of the Wnt/planar cell polarity pathway. In this study, we identified COBLL1 as a novel interaction partner of ROR1. COBLL1 shows clear bimodal expression with high levels in chronic lymphocytic leukemia patients with mutated IGHV and approximately 30% of chronic lymphocytic leukemia patients with unmutated IGHV. In the remaining 70% of chronic lymphocytic leukemia patients with unmutated IGHV, COBLL1 expression is low. Importantly, chronic lymphocytic leukemia patients with unmutated IGHV and high COBLL1 have an unfavorable disease course with short overall survival and time to second treatment. COBLL1 serves as an independent molecular marker for overall survival in chronic lymphocytic leukemia patients with unmutated IGHV. In addition, chronic lymphocytic leukemia patients with unmutated IGHV and high COBLL1 show impaired motility and chemotaxis towards CCL19 and CXCL12 as well as enhanced B-cell receptor signaling pathway activation demonstrated by increased PLCγ2 and SYK phosphorylation after IgM stimulation. COBLL1 expression also changes during B-cell maturation in non-malignant secondary lymphoid tissue with a higher expression in germinal center B cells than naïve and memory B cells. Our data thus suggest COBLL1 involvement not only in chronic lymphocytic leukemia but also in B-cell development. In summary, we show that expression of COBLL1, encoding novel ROR1-binding partner, defines chronic lymphocytic leukemia subgroups with a distinct response to microenvironmental stimuli, and independently predicts survival of chronic lymphocytic leukemia with unmutated IGHV.

Targeting Wnt signaling pseudokinases in hematological cancers

“…30,31 Furthermore, in a separate study, Cordon-bleu protein-like 1 (COBLL1) was identified as ROR1 binding partner and independent prognostic marker for CLL. 32 High levels of Wnt5a in CLL cells increase leukemic cell migration and chemotactic response compared to CLL cells with low or no Wnt5a expression and correlate F I G U R E 2 Gene expression of Wnt-related pseudokinases in healthy (left) and cancerous (right) hematological tissues derived from IST Online™ (ist.medisapiens.com). Data presented as box-whisker blots, where the bottom of the box is the 25th percentile of the data, the top of the box is the 75th percentile, and the horizontal line is the median.…”

“…Moreover, the ROR1 Pro‐rich domain interacts with hematopoietic lineage cell‐specific protein 1 (HS1) to drive F‐actin polymerization and cell migration, whereas the first Ser/Thr‐rich domain in ROR1 could bind the 14‐3‐3ζ protein to induce activation of RhoA/Rac1 and the enhancement of leukemic cell proliferation and migration . Furthermore, in a separate study, Cordon‐bleu protein‐like 1 (COBLL1) was identified as ROR1 binding partner and independent prognostic marker for CLL . High levels of Wnt5a in CLL cells increase leukemic cell migration and chemotactic response compared to CLL cells with low or no Wnt5a expression and correlate with worse prognosis .…”

Functional interdependence of the actin nucleator Cobl and Cobl-like in dendritic arbor development

“…Likewise, apart from dendritic branching of neurons studied here, there are no hints on any Cobl roles in functions that the Cobl-like (Cobll-1) gene has been linked to, such as diabetes and obesity ( Mancina et al, 2013 ; Sharma et al, 2017 ). Cobl-like was also suggested as biomarker for different cancer types ( Gordon et al, 2003 ; Gordon et al, 2009 ; Wang et al, 2013 ; Han et al, 2017 ; Plešingerová et al, 2018 ; Takayama et al, 2018 ), to be suppressed by Epstein-Barr virus infection ( Gillman et al, 2018 ) and to be involved in B-cell development ( Plešingerová et al, 2018 ) but there are no hints on Cobl roles in any of these processes.…”

Of Lymph Nodes and CLL Cells: Deciphering the Role of CCR7 in the Pathogenesis of CLL and Understanding Its Potential as Therapeutic Target

“…For example, interaction of wnt5 (A and B) or cordon-blue protein-like 1 (COBLL1) proteins with the receptor tyrosine kinase-like orphan receptor 1 (ROR1), a transmembrane receptor upregulated in CLL, activated pathways controlling cell polarity and migration. Specifically, ROR-1 activation increased basal migration and attenuated motility and chemotaxis toward CCL19 ( 159 , 160 ) suggesting a role of these axes in fine-tuning CLL movement along CCL19 gradients and shutting migration off once the right niche is found. Interestingly, in non-tumor cells, COBLL1 expression was also found to be higher in GC B cells than naïve and memory subsets, where a marked reduction in CCR7 expression is needed to facilitate CXCR5-guided access to the GC ( 129 , 161 , 162 ).…”