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INO, derived from ADO or IMP via ADA, has context-dependent immune effects ( These ectoenzymes, expressed by resident cells ( Figure 1 ), which sequentially generates ADPR, AMP, and ultimately immunosuppressive ADO ( Based on this background, we hypothesized that the dual role of CD38as a catalytic signaling receptor and a key component of the adenosinergic networkcontributes to immune dysregulation in MM ( In vitro assays using DARA and ISA were performed on primary MM cells ( + consumption and production of cADPR and ADPR, the latter entering the CD203a/CD73 axis to generate ADO, a mechanism we previously demonstrated using co-culture models ( 2 Materials and methods 2.1 Myeloma cells The LP-1 (CD38 + /CD203a /CD73 ) and BF01 (CD38 + /CD203a + /CD73 ) myeloma cell lines were established from patients with plasma cell leukemia ( Primary MM plasma cells were isolated from BM aspirates by immunomagnetic separation using anti-CD138 monoclonal antibody-coated microbeads (Miltenyi Biotec, Bergisch Gladbach, Germany) ( 2.2 Cells and microvesicle phenotypes Surface molecule expression on LP-1 and BF01 MM cell lines, primary human BM mononuclear cells, and primary MM cells was analyzed as previously described ( + /CD38 + /CD203a - /CD26 + ), maintained in IMDM medium supplemented with 10% FCS (Hyclone), 2 mM L-glutamine and antibiotics