Targeting BCL2 with venetoclax is a promising therapeutic strategy for "double-proteinexpression" lymphoma with MYC and BCL2 rearrangements.

The so-called "double-hit" and "double-protein-expression" lymphoma with MYC and BCL2 rearrangements is a rare, mature B-cell neoplasm characterized by a germinal center B-cell phenotype, abundant protein expression of MYC and BCL2, rapid disease progression, and a poor prognosis. In this study, we showed the potential benefit of the BCL2 inhibitor venetoclax in the treatment of this disease. Immunohistochemical studies of the lymphoma tissues confirmed that overexpression of MYC and BCL2 was observed more frequently in this subtype than in other germinal center B-cell-like diffuse large B-cell lymphomas. In contrast, another pro-survival protein MCL1 was less expressed in this subtype, even when compared with its expression in the non-"double-hit" and "double-protein-expression" type. Furthermore, in vitro studies using two "double-hit" and "double-protein-expression" lymphoma-derived cell lines, Karpas231 and OCI-Ly8, clearly showed that a low concentration of venetoclax, but not the MCL1 inhibitor S63845, was sufficient to induce apoptosis in the two lines, compared with in other germinal center B-cell-derived cell lines, BJAB and SU-DHL10. These results indicate that the survival of this type of lymphoma depends predominantly on BCL2 rather than on MCL1. Unexpectedly, we found that venetoclax not only disrupts the interaction between BCL2 and the pro-apoptotic protein BIM, but also leads to dephosphorylation of BCL2 and further downregulates MCL1 protein expression, probably through modulation of the protein phosphatase 2A B56α activity in Karpas231 and OCI-Ly8. Indeed, a low concentration of venetoclax induced substantial apoptosis in the primary lymphoma cells, regardless of high protein expression of MCL1 associated with venetoclax resistance. Venetoclax clearly triggers the signal transduction related to BCL2 and MCL1 in "double-hit" and "double-protein-expression" lymphoma cells.

Expression of activating natural killer-cell receptors is a hallmark of the innate-like T-cell neoplasm in peripheral T-cell lymphomas.

Peripheral T- or natural killer (NK)-cell lymphomas are rare and difficult-to-recognize diseases. It remains arduous to distinguish between NK cell- and cytotoxic T-lymphocyte-derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK-cell receptors and examined the expression using immunohistochemistry in 22 cases with T- and NK-cell neoplasms comprising angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase (ALK)-positive and -negative anaplastic large-cell lymphomas, extranodal NK/T-cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T-cell lymphoma, aggressive NK-cell leukemia, and other peripheral T-cell lymphomas. Inhibitory receptor leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK-cell receptors were expressed predominantly in TIA-1-positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK-cell neoplasms and cytotoxic T-lymphocyte-derived lymphomas including monomorphic epitheliotropic intestinal T-cell lymphoma. One Epstein-Barr virus-harboring cytotoxic T-lymphocyte-derived lymphoma mimicking extranodal NK/T-cell lymphoma, nasal type lacked these NK-cell receptors, indicating different cell origin from NK and innate-like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log-rank test, P = .024). We propose that the presence of activating NK-cell receptors may provide new insights into understanding peripheral T-cell lymphomas and characterizing them as innate-like T-cell neoplasm.

Renoprotective effect of the xanthine oxidoreductase inhibitor Topiroxostat under decreased angiotensin II type 1a receptor expression.

The aim of this study was to confirm the renoprotective effect of xanthine oxidoreductase (XOR) inhibitor, topiroxostat, compared with another XOR inhibitor, febuxostat, under decreased angiotensin II type 1a (AT1a) receptor expression in the model of renal injury caused by adenine. To evaluate the degree of tubular damage using urinary liver-type fatty acid-binding protein (L-FABP) under decreased AT1a expression, we used AT1a receptor knockdown hetero and human L-FABP chromosomal transgenic (Tg) mice (AT1a+/-L-FABP+/-). Male AT1a+/-L-FABP+/- mice were divided into two groups: the adenine diet group (n = 40) was given a diet containing only 0.2% w/w adenine, and the normal diet group (n = 5) was given a normal diet. When renal dysfunction was confirmed in the adenine diet group 4 weeks after starting the diet, the adenine diet group was further divided into five groups. The adenine diet group (n = 8) was continuously given only the adenine diet. Each group receiving high-dose (3mg/kg) or low-dose (1mg/kg) topiroxostat (Topiroxostat-H group, n = 8, Topiroxostat-L group, n = 8) or febuxostat (Febuxostat-H group, n = 8, Febuxostat-L group, n = 8) was given the adenine diet including the drug for another 4 weeks. The levels of renal XOR, renal dysfunction, urinary L-FABP, tubulointerstitial damage, hypoxia, and oxidative stress were decreased or attenuated after treatment with topiroxostat or febuxostat compared with the adenine diet group. Furthermore, antioxidant capacity was maintained owing to these treatments. In conclusion, topiroxostat and febuxostat attenuated renal damage under decreased AT1a expression in the adenine-induced renal injury model.