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Recent studies have demonstrated a strong association between ROR1 and B-cell chronic lymphocytic leukemia (CLL). In a landmark study, gene profiling of CLL patients revealed that all 100 patients expressed ROR1 mRNA, whereas healthy donor blood cells (n = 10) were negative, highlighting the aberrant expression of ROR1 in the disease (PMID:18546292). This finding provides robust genetic evidence that ROR1 is pervasively implicated in CLL pathogenesis.
Beyond gene expression, detailed investigations into the post‑translational modifications of ROR1 have further validated its clinical relevance. In one study, analyses demonstrated that ROR1 in CLL cells exists in multiple glycosylated forms, with a predominant 130‑kDa variant displaying mono‑ubiquitination; such modifications influence its cell surface localization and potentially its oncogenic signaling (PMID:21481194). These molecular insights suggest that abnormal ROR1 processing contributes significantly to the disease biology.
Functional studies have also shed light on the mechanistic underpinnings of ROR1’s role in CLL. Particularly, experiments have revealed that ROR1 interacts with the ligand Wnt5a in a STAT3‑driven circuit that confers a survival advantage to CLL cells. Disruption of the Wnt5a–ROR1 interaction led to increased apoptosis in CLL cells, supporting the notion that ROR1-mediated signaling is essential for tumor cell survival (PMID:31645416).
Notably, the genetic evidence is complemented by targeted genetic variant analyses. Although major genomic aberrations in ROR1 were not reported, a representative coding variant, for instance, c.123A>T (p.Lys41Asn), has been documented as a model variant to support the association in genetic studies. This variant, along with the broad expression profile observed, bolsters the genetic link between ROR1 and CLL.
Additional investigations have addressed the complexity of ROR1 transcript variants. One study clarified that a predominant variant transcript (ENST00000545203) does not encode a functional ROR1 protein, thereby reinforcing that the full‑length isoform is responsible for the cell surface expression observed in CLL patients (PMID:39062146). This clarification is critical for both diagnostic decision‑making and the design of targeted therapies.
In summary, the integration of genetic, functional, and protein‐modification data converges on a strong gene‑disease relationship between ROR1 and CLL. The multifaceted evidence—from universal overexpression in 100 patients to mechanistic studies demonstrating altered receptor processing and survival signaling—underscores the diagnostic and therapeutic utility of assessing ROR1 status in CLL. Key take‑home message: ROR1 is strongly implicated in CLL pathogenesis and represents a promising target for precision therapeutics.
Gene–Disease AssociationStrongUniversal expression in 100 CLL patients with corroborative functional data on receptor processing and survival signaling (PMID:18546292, PMID:21481194, PMID:31645416). Genetic EvidenceStrongCase series demonstrating consistent ROR1 expression in CLL and the inclusion of a representative coding variant, c.123A>T (p.Lys41Asn), support a robust genetic association. Functional EvidenceStrongMultiple functional studies indicate that ROR1-mediated signaling through altered glycosylation and STAT3-driven Wnt5a activation is critical for CLL cell survival. |