JAK-STAT3 Pathway Regulates CD38 Expression on Multiple Myeloma Cells

In this study, we evaluated the impact of bone marrow stromal cells (BMSCs) from MM patients on CD38 expression and anti-CD38 Antibody-induced ADCC.We first cultured MM cells (RPMI8226, MM.1S, MOLP8) with culture supernatant from BMSCs and measured CD38 expression by flow cytometry. A significant reduction of CD38 expression on all MM cell lines was noted in a time-dependent fashion. For example, CD38 expression (mean fluorescence intensity) was reduced 44%, 32%, and 42% on RPMI8226, MM.1S and MOLP8 cells, respectively, after 48 h culture with BMSC supernatants. To identify mediators of this effect, we next examined the effect of MM-relevant cytokines (IL-6, IGF-1, IL-1β) on CD38 expression. Importantly, IL-6 significantly downregulated CD38 expression on MM cells whereas IGF-1 or IL-1β had no significant impact. We further performed quantitative real-time PCR to evaluate CD38 mRNA level in RPMI8226 and MOLP8 cells cultured with BMSC supernatant or IL-6 and confirmed that CD38 transcript was downregulated by both treatments in these cells. Since IL-6, but not IGF-1, downregulated CD38, we hypothesized that JAK-STAT3 pathway might mediate this IL-6 triggered downregulation of CD38 expression. As with IL-6 treatment, transfection of MM.1S cells with constitutively active STAT3 significantly reduced CD38 expression. Conversely, knockdown of STAT3 by siRNA partially restored CD38 expression on RPMI8226 cells in the presence of IL-6. Moreover, we cultured RPMI8226 and MM...
Source: Blood - Category: Hematology Authors: Tags: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster III Source Type: research