Jin Asano

The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells

Bone marrow stromal cells (BMSCs) and osteoclasts (OCs) confer multiple myeloma (MM) cell survival through elaborating factors. We demonstrate herein that IL-6 and TNF family cytokines, TNFα, BAFF and APRIL, but not IGF-1 cooperatively enhance the expression of the serine/threonine kinase Pim-2 in MM cells. BMSCs and OCs upregulate Pim-2 expression in MM cells largely via the IL-6/STAT3 and NF-κB pathway, respectively. Pim-2 short interfering RNA reduces MM cell viability in cocultures with BMSCs or OCs. Thus, upregulation of Pim-2 appears to be a novel anti-apoptotic mechanism for MM cell survival. Interestingly, the mammalian target of rapamycin inhibitor rapamycin further suppresses the MM cell viability in combination with the Pim-2 silencing. The Pim inhibitor (Z)-5-(4-propoxybenzylidene) thiazolidine-2, 4-dione and the PI3K inhibitor LY294002 cooperatively enhance MM cell death. The Pim inhibitor suppresses 4E-BP1 phosphorylation along with the reduction of Mcl-1 and c-Myc. Pim-2 may therefore become a new target for MM treatment.

Therapy with bortezomib plus dexamethasone induces osteoblast activation in responsive patients with multiple myeloma.

Bortezomib is a novel proteasome inhibitor that has shown marked antitumor effects in patients with multiple myeloma (MM). We evaluated the feasibility and efficacy of bortezomib plus dexamethasone (BD) therapy and assessed bone metabolism in relapsed or refractory MM. Fourteen patients received 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 along with 20 mg/dose of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 in a 21-day cycle. After 1 to 3 cycles of BD therapy, 9 patients (64%) achieved an objective response (5 very good partial responses and 4 partial responses). Notably, a rapid increase in the serum concentration of alkaline phosphatase (ALP) was observed in 6 of the treatment-responsive patients. Moreover, serum levels of bone-formation markers (bone-specific ALP and osteocalcin) significantly increased in 5 and 2 responsive patients, respectively. Radiographic examination showed improvement in bone lesions, suggesting that BD therapy induces osteoblast activation in responders. Adverse events included thrombocytopenia of grades 1 to 3, peripheral neuropathy of grades 1 to 2, and grade 3 ileus and were transient and manageable. Although severe lung injury has been reported among Japanese patients treated with bortezomib, no pulmonary complications were observed during BD therapy. Our results suggest that BD therapy is a safe and promising therapeutic approach for Japanese patients with MM.

Functional Analysis of vif Genes Derived from Various Primate Immunodeficiency Viruses

Replication property in cells of human and simian immunodeficiency viruses (HIVs and SIVs) lacking intact vif gene was evaluated. Of 10 vif mutants constructed in vitro of the major four HIV/SIV groups, only those derived from HIV-1 and HIV-2/SIVmac displayed replication defect. The cell lines non-permissive for the vif mutants of HIV-1 and SIVmac were found to be different. To determine whether Vif is exchangeable between HIV-1 and SIVmac, chimeric virus clones with respect to the vif gene were constructed and virus replication in the cells non-permissive for the vif mutant viruses was monitored. Productive infection in these cells of chimeric viruses clearly indicated that Vif is functionally exchangeable, and that Vifs of different virus origin act through a similar mechanism.