Genetic evidence of PTPN22 effects on chronic lymphocytic leukemia

To the editor:

The recent article by Negro et al represents a thorough investigation into the effect of Lyp, the gene product of PTPN22, on BCR signaling in the pathogenesis and progression of chronic lymphocytic leukemia (CLL).¹  This study shows that increased Lyp enhances Akt, a serine/threonine kinase involved in cell survival and tumorigenesis, despite a negative effect on proximal BCR signaling molecules including Lyn, Syk, and p38MAPK (inhibition of p38MAPK decreases activation-induced lymphoma B-cell apoptosis). The effect is mediated through reduced recruitment/activation of SHIP. Therefore, Negro et al reveal a critical Lyp-mediated mechanism involved in CLL susceptibility.

Over the past decade, the PTPN22 gene has received considerable attention because of its role in autoimmunity susceptibility, response to infection, and systemic inflammation. A diverse set of studies have demonstrated that the R620W missense polymorphism in PTPN22 (rs2476601) is involved in numerous immune-related diseases, including type 1 diabetes, rheumatoid arthritis, autoimmune thyroiditis, systemic lupus erythematosus, primary antibody deficiency, and bacterial infection.^2-4  Functional studies have painted a complex picture of how Lyp*620W affects lymphocyte function/activity: reduced Lyp protein levels, obstruction of Csk binding, lower TCR-induced Tyr-phosphorylation of Lyp, inhibited BCR-mediated apoptosis, and reduced pruning of autoreactive B cells are all proposed mechanisms.^5-8  The discovery of whether Lyp*620W confers protective or susceptible effects on CLL (ie, significantly increased/decreased in CLL cases over controls) may not only provide insight into CLL susceptibility, but also may illuminate Lyp-mediated signaling. The Negro et al study genotyped rs2476601 in a limited number of Italian CLL cases (n = 29) with 1 identified carrier, which is consistent with the expected low 620W allele frequency within an Italian population compared with northern/western Europeans (HapMap).¹  However, matched controls are absent and this small substudy suffers from less than 10% power to detect a relative risk of 1.4.

To further investigate the role of the PTPN22 gene in CLL, we correlated rs2476601 genotypes (or a surrogate of rs2476601) with CLL using data from 2 unique studies derived from northern/western Europeans. In the Personalized Medicine Research Project (PMRP) cohort,⁹  37 of the 4235 genotyped subjects were diagnosed with CLL based on ICD9 codes within patient electronic medical records. The frequency of 620W carriers was significantly increased in CLL cases compared with 4199 controls (PMRP: 32% vs 18%, respectively, P = .033; Table 1). The Genetic Epidemiology of CLL (GEC) Consortium genotyped a proxy single-nucleotide polymorphism (rs6679677) in complete linkage disequilibrium (HapMap-CEU r² = 1) with rs2476601 in 407 CLL cases and 296 controls,¹⁰  producing results supporting the PMRP finding (GEC: 24% vs 17%, P = .019; Table 1). Whereas these results corroborate the Negro et al report, additional verification of these preliminary findings is needed to draw strong conclusions. Given previous studies showing the 620W allele generating decreased CD27⁺ B-cell proliferation independently of apoptotic processes,⁵  these results raise the possibility that 620W pro-CLL effects may be mediated through nonproliferative mechanisms. Because Lyp exercises its pathogenic action across multiple diseases and as Lyp-targeted therapies continue to develop, understanding the potential role of PTPN22 variation in CLL will be essential as we elucidate the molecular pathogenesis of CLL and other immunologic diseases/conditions.