Subject(s)
5'-Nucleotidase , Apyrase , Immune Tolerance , Immunosuppression Therapy , Sezary Syndrome , Skin Neoplasms , T-Lymphocytes , Humans , 5'-Nucleotidase/metabolism , Adenosine/metabolism , Adenosine Triphosphate/metabolism , Apyrase/metabolism , Sezary Syndrome/metabolism , Sezary Syndrome/therapy , Skin Neoplasms/metabolism , Skin Neoplasms/therapyABSTRACT
CD157/BST-1 (a member of the ADP-ribosyl cyclase family) is expressed at variable levels in 97% of patients with acute myeloid leukemia (AML), and is currently under investigation as a target for antibody-based immunotherapy. We used peripheral blood and bone marrow samples from patients with AML to analyse the impact of CD157-directed antibodies in AML survival and in response to cytarabine (AraC) ex vivo. The study was extended to the U937, THP1 and OCI-AML3 AML cell lines of which we engineered CD157-low versions by shRNA knockdown. CD157-targeting antibodies enhanced survival, decreased apoptosis and reduced AraC toxicity in AML blasts and cell lines. CD157 signaling activated the PI3K/AKT/mTOR and MAPK/ERK pathways and increased expression of Mcl-1 and Bcl-XL anti-apoptotic proteins, while decreasing expression of Bax pro-apoptotic protein, thus preventing Caspase-3 activation. The primary CD157-mediated anti-apoptotic mechanism was Bak sequestration by Mcl-1. Indeed, the Mcl-1-specific inhibitor S63845 restored apoptosis by disrupting the interaction of Mcl-1 with Bim and Bak and significantly increased AraC toxicity in CD157-high but not in CD157-low AML cells. This study provides a new role for CD157 in AML cell survival, and indicates a potential role of CD157 as a predictive marker of response to therapies exploiting Mcl-1 pharmacological inhibition.
Subject(s)
ADP-ribosyl Cyclase/metabolism , Antigens, CD/metabolism , Drug Resistance, Neoplasm , Leukemia, Myeloid, Acute/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , ADP-ribosyl Cyclase/genetics , Adult , Aged , Aged, 80 and over , Antigens, CD/genetics , Antimetabolites, Antineoplastic/toxicity , Apoptosis , Cells, Cultured , Cytarabine/toxicity , Female , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Humans , MAP Kinase Signaling System , Male , Middle Aged , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidines/pharmacology , THP-1 Cells , Thiophenes/pharmacologyABSTRACT
: Human CD157/BST-1 and CD38 are dual receptor-enzymes derived by gene duplication that belong to the ADP ribosyl cyclase gene family. First identified over 30 years ago as Mo5 myeloid differentiation antigen and 10 years later as Bone Marrow Stromal Cell Antigen 1 (BST-1), CD157 proved not to be restricted to the myeloid compartment and to have a diversified functional repertoire ranging from immunity to cancer and metabolism. Despite being a NAD+-metabolizing ectoenzyme anchored to the cell surface through a glycosylphosphatidylinositol moiety, the functional significance of human CD157 as an enzyme remains unclear, while its receptor role emerged from its discovery and has been clearly delineated with the identification of its high affinity binding to fibronectin. The aim of this review is to provide an overview of the immunoregulatory functions of human CD157/BST-1 in physiological and pathological conditions. We then focus on CD157 expression in hematological tumors highlighting its emerging role in the interaction between acute myeloid leukemia and extracellular matrix proteins and its potential utility for monoclonal antibody targeted therapy in this disease.
