Targeting netrin‐1/DCC interaction in diffuse large B‐cell and mantle cell lymphomas

Abstract

DCC (Deleted in Colorectal Carcinoma) has been demonstrated to constrain tumor progression by inducing apoptosis unless engaged by its ligand netrin‐1. This has been shown in breast and colorectal cancers; however, this tumor suppressive function in other cancers is not established. Using a transgenic mouse model, we report here that inhibition of DCC‐induced apoptosis is associated with lymphomagenesis. In human diffuse large B‐cell lymphoma (DLBCL), an imbalance of the netrin‐1/DCC ratio suggests a loss of DCC‐induced apoptosis, either via a decrease in DCC expression in germinal center subtype or by up‐regulation of netrin‐1 in activated B‐cell (ABC) one. Such imbalance is also observed in mantle cell lymphoma (MCL). Using a netrin‐1 interfering antibody, we demonstrate both in vitro and in vivo that netrin‐1 acts as a survival factor for ABC‐DLBCL and MCL tumor cells. Together, these data suggest that interference with the netrin‐1/DCC interaction could represent a promising therapeutic strategy in netrin‐1‐positive DLBCL and MCL.

Understanding the participation of GREM1 polymorphisms in nonsyndromic cleft lip with or without cleft palate in the Brazilian population

“…Indeed, targeted deletion of Gremlin 1 in mice leads to a loss of kidneys due to complete elimination of the metanephric mesenchyme by apoptosis (Michos et al, ). Recently, we demonstrated protective effects of variant rs1880646, which is located in NTN1 (Netrin 1), a gene associated with apoptotic phenotypes (Broutier et al, ; Lahlali et al, ), with NSCL±P in this same Brazilian sample (Machado et al, ). Together GREM1 and NTN1 SNP may interact, reducing NSCL±P risk.…”

“…Recently, we demonstrated protective effects of variant rs1880646, which is located in NTN1 (Netrin 1), a gene associated with apoptotic phenotypes (Broutier et al, 2016;Lahlali et al, 2016), with NSCLAEP in this same Brazilian sample . Together GREM1 and NTN1 SNP may interact, reducing NSCLAEP risk.…”

“…Recently, we demonstrated a protective association of variant rs1880646 in NTN1 at 17p13 with NSCL±P in this same case‐control sample (Machado et al, ). As rs1880646 in NTN1 and SNP in GREM1 showed similar protective effects and both genes are associated with apoptotic phenotypes (Broutier et al, ; Church et al, ; Costello et al, ; Michos et al, ), which are essentials for normal embryogenesis, we further performed pairwise SNP‐SNP interaction analysis. Three of the GREM1 SNP (rs16969862, rs16969681, and rs16969816) revealed significant interactions with rs1880646 in NTN1 , with p values of interactions resisted to Bonferroni adjustment for multiple testing and to 1,000 permutation test (Table ).…”

“…Furthermore, the detection of interactions between SNP within distinct chromosomes, not in linkage disequilibrium, suggests that these interactions are neither sporadic nor the spurious artifacts of genotyping. Previous studies demonstrated that GREM1 and NTN1 are expressed in the craniofacial region during early development of the palate (Leslie et al, ; Ludwig et al, ) and functional analyses suggest that encoded proteins are related to apoptosis (Broutier et al, ; Church et al, ; Costello et al, ; Lahlali et al, ; Michos et al, ). Although genetic association studies often focus on coding SNP, particularly nonsynonymous SNP resulting in amino acid changes because they are likely to be functional, recent studies have showed that SNP in other regions, including in intronic regions as those in GREM1 and NTN1 , may also have regulatory functional consequences.…”

Age‐related heterogeneity of Burkitt lymphoma: response to Mbulaiteye and Anderson

“…These should be confirmed in larger series. Recently, Broutier et al () confirmed a tumour suppressor role for DCC in diffuse large B‐cell lymphoma (DLBCL). They demonstrated that an imbalance in the netrin‐1 (NTN1)/DCC expression ratio is associated with aggressive lymphoma, and DCC loss occurs in germinal centre DLBCL.…”