A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling

A BAFF receptor mutation associated with non-Hodgkin lymphoma provides new insight into the proximal players of normal BAFF-R signaling

Lack of JAK2 activating non-synonymous mutations in diffuse large B-cell tumors: JAK2 deregulation still unexplained

Deregulated JAK2 signaling plays an important role in the pathogenesis of myeloproliferative neoplasms (MPN). We and others have shown constitutive activation of JAK2 and STAT3 in diffuse large B cell lymphomas (DLBCL). We sought to determine the mechanism of JAK2 signaling in DLBCL tumors with a genetic approach. The most common JAK2 activating mutation present in most MPNs is V617F (exon 14 within the pseudokinase-domain); however, this mutation is absent in lymphoid malignancies. We bi-directionally sequenced all the domains of the JAK2 gene and performed mutational analysis. No novel non-synonymous mutations were detected in the 40 DLBCL tumors tested. However synonymous and non-synonymous single nucleotide polymorphism (SNPs) were detected within the exons 6, 9 and 19 in the majority of patients. Taken together, these data suggest that other mechanisms for altered JAK2 signaling aside from activating JAK2 mutations are present in DLBCL. Targeting JAK2 activation could be an important therapeutic target for DLBCL. Indeed, the JAK2 inhibitor ruxolitinib is now approved for the treatment of MPN. Our study indicates that JAK2 targeted clinical trials in lymphoma should not be confined to only JAK2 mutation cases but rather based on pathway activation

Inhibiting IL-2 Signaling and the Regulatory T-cell Pathway Using Computationally Designed Peptides

Background Increased serum levels of soluble interleukin-2 (IL-2) receptor alpha (sIL-2Rα) are an indicator of poor prognosis in patients with B-cell non-Hodgkin lymphoma (NHL). By binding to IL-2, sIL-2Rα upregulates Foxp3 expression and induces the development of regulatory T (Treg) cells. Methods To inhibit the binding of IL-2 to sIL-2Rα with the goal of suppressing the induction of Foxp3 and decreasing Treg cell numbers, we developed peptides by structure-based computational design to disrupt the interaction between IL-2 and sIL-2Rα. Each peptide was screened using an enzyme-linked immunosorbent assay (ELISA), and 10 of 22 peptides showed variable capacity to inhibit IL-2/sIL-2Rα binding. Results We identified a lead candidate peptide, CMD178, which consistently reduced the expression of Foxp3 and STAT5 induced by IL-2/sIL-2Rα signaling. Furthermore, production of cytokines (IL-2/interferon gamma [IFN-γ]) and granules (perforin/granzyme B) was preserved in CD8+ T cells co-cultured with IL-2–stimulated CD4+ T cells that had been pretreated with CMD178 compared to CD8+ cells co-cultured with untreated IL-2–stimulated CD4+ T cells where it was inhibited. Conclusions We conclude that structure-based peptide design can be used to identify novel peptide inhibitors that block IL-2/sIL-2Rα signaling and inhibit Treg cell development. We anticipate that these peptides will have therapeutic potential in B-cell NHL and other malignancies