畑野 かおる

Multiple myeloma ( MM) is incurable, mainly because of cell adhesion-mediated drug resistance (CAM-DR). In this study, we performed functional screening using short hairpin RNA (shRNA) to de. ne the molecule(s) responsible for CAM-DR of MM. Using four bona. de myeloma cell lines (KHM-1B, KMS12-BM, RPMI8226 and U266) and primary myeloma cells, we identified CD29 (beta 1-integrin), CD44, CD49d (alpha 4-integrin, a subunit of VLA-4), CD54 ( intercellular adhesion molecule-1 (ICAM-1)), CD138 (syndecan-1) and CD184 (CXC chemokine receptor-4 (CXCR4)) as major adhesion molecules expressed on MM. shRNA-mediated knockdown of CD49d but not CD44, CD54, CD138 and CD184 significantly reversed CAM-DR of myeloma cells to bortezomib, vincristine, doxorubicin and dexamethasone. Experiments using blocking antibodies yielded almost identical results. Bortezomib was relatively resistant to CAM-DR because of its ability to specifically down-regulate CD49d expression. This property was unique to bortezomib and was not observed in other anti-myeloma drugs. Pretreatment with bortezomib was able to ameliorate CAM-DR of myeloma cells to vincristine and dexamethasone. These results suggest that VLA-4 plays a critical role in CAM-DR of MM cells. The combination of bortezomib with conventional anti-myeloma drugs may be effective in overcoming CAM-DR of MM.

A 35-year-old male, blood group B, Rh(D)+ type, received an allogeneic peripheral blood stem cell (PBSC) transplant after a non-myeloablative regimen of fludarabine and cyclophosphamide for resistant gammadelta cutaneous T-cell lymphoma (CTCL). The donor was his HLA-identical brother, blood group O, Rh(D)+ type. Graft-versus-host disease (GVHD) prophylaxis was performed with cyclosporine alone. On day +8, massive immune hemolysis occurred, followed by acute renal failure. Hemodialysis was performed eight times until recovery of renal function on day +24. The risk of delayed immune hemolysis after non-myeloablative allogeneic PBSC transplantation with minor ABO-incompatibility must be considered.