Fumio Imanaka

A possible role for the loss of CD27–CD70 interaction in myelomagenesis

Summary. CD27 is a marker of memory B cells and its interaction with its ligand, CD70, is very important for differentiation into plasma cells. Although CD27 is detected on normal plasma cells, its expression is significantly reduced with the progression of multiple myeloma (MM), including monoclonal gammopathy of undetermined significance (MGUS). CD27+ myeloma cells are thought to represent an early phase of myeloma, as CD27+ plasma cells from MM patients were found to be composed of normal plasma cells (CD19+/CD38++) and myeloma cells (CD19–/CD38++), and monoclonality was detected in the CD27+/CD38++ fraction. Given that the lack of CD27 on plasma cells is related to myelomagenesis and that the pro‐apoptotic protein Siva is thought to bind to the cytoplasmic tail of CD27, we analysed alterations of cell growth and genes caused by co‐culturing CD27‐transfected myeloma cell lines (U266, KMS‐5) with CD70‐transfected NIH3T3 cells. CD27–CD70 interaction could not induce apoptosis in either type of myeloma transfectant, and binding between Siva and CD27 was not detected. cDNA microarray (human apoptosis CHIP) analysis showed a significant upregulation of expression of the ectodermal neural cortex 1 (ENC1) gene by CD27–CD70 interaction compared with CD27 transfection alone. These findings show that the relationship between the loss of CD27 and oncogenesis of plasma cells is not simple. It remains unclear whether the lack of CD27 leads to evasion of apoptosis.

Initial expression of interferon alpha receptor 2 (IFNAR2) on CD34-positive cells and its down-regulation correlate with clinical response to interferon therapy in chronic myelogenous leukemia

Abstract:  In order to investigate the mechanism of interferon‐α (IFNα) action in the treatment of chronic myelogenous leukemia (CML), we examined surface expressions of both type I interferon receptor 1 (IFNAR1) and 2 (IFNAR2) subunits on CD34‐positive cells in bone marrow (BM) in a total of 57 CML patients. Initial cell‐surface IFNAR2 expression at diagnosis assessed by flow cytometry widely distributed but showed overall significantly higher expression in CML patients when compared with normal controls. In 15 fresh patients who subsequently received IFNα therapy, IFNAR2 expression at diagnosis was significantly higher in cytogenetic good responders than in poor responders. Down‐regulation of IFNAR2 expression during IFNα therapy was observed only in good responders but not in poor responders. In addition to protein level, both initial high IFNAR2c mRNA expression level and its down‐regulation during IFNα therapy, in purified CD34‐positive cells, were also observed only in good responders. In contrast to IFNAR2, cell‐surface IFNAR1 expression was generally lower than IFNAR2, and correlation between either the pretreatment level or down‐regulation of IFNAR1 and clinical response was not evident. With in vitro IFNα stimulation, CD34‐positive cells showed down‐regulations of cell‐surface IFNAR2, and IFNAR1 to a lesser extent, in one good‐responder patient, but not in one poor‐responder patient. Serum soluble interferon receptor (sIFNR) was higher in untreated CML patients than in normal controls, without any correlation with clinical response to IFNα. Thus, the pretreatment protein and mRNA expression levels of IFNAR2 and their down‐regulations during IFNα therapy correlate well with IFNα response in CML patients.