AP1-dependent galectin-1 expression delineates classical hodgkin and anaplastic large cell lymphomas from other lymphoid malignancies with shared molecular features

Galectin-1 is an immunomodulatory glycan-binding protein regulated by an AP1-dependent enhancer in Hodgkin Reed-Sternberg cells. We recently found that Reed Sternberg cell Gal-1 promotes the immunosuppressive T helper2/ T-regulatory cell-skewed microenvironment in classic Hodgkin lymphoma (cHL). We sought to investigate whether the the coordinate expression of activated AP1 pathway components and Gal-1 serves as a diagnostic signature of cHL. In addition, because there are common signaling and survival pahtways in cHL and additional non-Hodgkin lymphomas, we also evaluated whether the AP1/Gal1 signature is shared by other molecularly or morphologically related lymhomas. Our findings establish a functional AP1 signature that incluses Gal-1 expression in cHL and ALCL, and suggests a common mechanmism for tumor immunotolerance in these diseases. In addition, the combination of Gal1 and c-Jun serve as diagnostic biomarkers that delineate cHL and ALCL from other lymphomas with shared morphologic and/or molecular features.Fil: Rodig, Scott J.. Harvard Medical School; Estados UnidosFil: Ouyang, Jing. Dana Farber Cancer Institute; Estados UnidosFil: Juszczynski, Przemyslaw. Dana Farber Cancer Institute; Estados UnidosFil: Currie, Treeve. Harvard Medical School; Estados UnidosFil: Law, Kenneth. Harvard Medical School; Estados UnidosFil: Neuberg, Donna S.. Dana Farber Cancer Institute; Estados UnidosFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Shipp, Margaret A.. Dana Farber Cancer Institute; Estados UnidosFil: Kutok, Jeffery L.. Harvard Medical School; Estados Unido

Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index.

Novel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we further investigate GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify eleven GPR151 putative loss-of-function (plof) variants, three of which are present at homozygosity (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7), with a cumulative allele frequency of 2.2%. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits and find that GPR151 deficiency in complete human knockouts is not associated with clinically significant differences in these traits. Relative to Gpr151+/+ mice, Gpr151-/- animals exhibit no difference in body weight on normal chow and higher body weight on a high-fat diet. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach to treatment of obesity

Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index.

Novel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we further investigate GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify eleven GPR151 putative loss-of-function (plof) variants, three of which are present at homozygosity (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7), with a cumulative allele frequency of 2.2%. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits and find that GPR151 deficiency in complete human knockouts is not associated with clinically significant differences in these traits. Relative to Gpr151+/+ mice, Gpr151-/- animals exhibit no difference in body weight on normal chow and higher body weight on a high-fat diet. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach to treatment of obesity

Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders

Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBVdriven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV proteins, including latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV-transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy, and administration of EBV-specific cytotoxic T cells. In the present study, we report that EBV-transformed lymphoblastoid Bcell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydratebinding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4 Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression, and the combination of LMP2A and LMP1 was additive. In addition, small interfering RNA (siRNA)–mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was dependent on both activating protein 1 (AP-1) and PI3K. A newly developed neutralizing Gal1 mAb selectively inhibited Gal1-mediated apoptosis of EBV-specific CD8 T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors.Fil: Ouyang, Ying. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosFil: Juszczynski, Przemyslaw. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosFil: Rodig, Scott J.. Brigham and Women’s Hospital. Department of Pathology; Estados UnidosFil: Green, Michael R.. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosFil: O´ Donnell, Evan. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosFil: Currie, Treeve. Brigham and Women’s Hospital. Department of Pathology; Estados UnidosFil: Armant, Myriam. Immune Disease Institute/Harvard Medical School. Center for Human Cell Therapy; Estados UnidosFil: Takeyama, Kunihiko. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosFil: Monti, Stefano. Broad Institute; Estados UnidosFil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Ritz, Jerome. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosFil: Kutok, Jeffery L.. Brigham and Women’s Hospital. Department of Pathology; Estados UnidosFil: Shipp, Margaret A.. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unido