P2RY8 (P2Y Receptor Family Member 8)

CD8+ T and NK cells exhibit functional polarization and altered cellular communication indicative of augmented anti-tumor immunity in ccRCC. The immune-cell-derived 10-gene signature provides a reliable prognostic tool and guides personalized therapy.

Despite extensive structural and pharmacological studies, the functional impact of missense variation across GPCRs remains poorly understood, particularly for receptors involved in immune regulation. In this issue of Cell Genomics, LaFlam et al.1 systematically map P2RY8 variant functions using deep mutational scanning (DMS) combined with structural biology approaches, revealing pleiotropy and mechanisms linking GPCR variation to B cell confinement and lymphoma.

This rare presentation underlines the diagnostic challenges of acute leukaemias. The patient was finally treated with azacitidine and venetoclax.

Moreover, combinatorial knockout of P2RY8 (trafficking) and GNAS (effector function) further enhanced overall tumor control, demonstrating that genetic modifications targeting distinct T cell phenotypes can be combined to improve therapeutic potency. This flexible and scalable in vivo screening platform can be adapted to diverse tumor models and pooled CRISPR libraries, enabling future discovery of genetic strategies that equip T cell therapies to overcome barriers imposed by solid tumors.

We also discuss therapeutic strategies that aim at balancing individualized treatment approaches with optimized supportive care to reduce toxicity and minimize relapse risk. This case underlines the importance of comprehensive molecular diagnostics, serial MRD monitoring, and personalized multidisciplinary care in DS-ALL.

However, the contribution of CRLF2 overexpression to long-term risk remains uncertain. At 54 months since diagnosis, he remains in good health following his initial complete response.

P1/2, N=26, Recruiting, Princess Maxima Center for Pediatric Oncology | Trial completion date: Oct 2031 --> Feb 2032 | Not yet recruiting --> Recruiting | Trial primary completion date: Oct 2031 --> Feb 2032

We applied the deep mutational scanning results to both improve computational variant effect predictions and to characterize the phenotype of germline variants and lymphoma-associated variants. Together, our results demonstrate the power of integrating deep mutational scanning, structure determination, and in silico prediction to advance the understanding of a receptor important in human health.

The targeted sequencing approach can help in detecting known and novel fusions in B-ALL, novel breakpoints in the known fusions, gene deletions as oncogenic/novel isoforms and CRLF2 expression.

Our study highlights the importance of OXPHOS activity in CD8+TILs exhaustion and suggests its possible regulatory mechanism, which is feasible in clinical evaluation and beneficial for novel immunotherapeutic approaches in DLBCL.

CRLF2 gene is overexpressed in those with IL3RA, CSF2RA and P2RY8 gene deletions. However, CRLF2 overexpression is not associated with survival outcome.