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1.
Mol Cancer Res ; 18(4): 632-643, 2020 04.
Article in English | MEDLINE | ID: mdl-31974290

ABSTRACT

The signaling lymphocytic activation molecule family 3 (SLAMF3) is a member of the immunoglobulin superfamily expressed on T, B, and natural killer cells and modulates the activation and cytotoxicity of these cells. SLAMF3 is also expressed on plasma cells from patients with multiple myeloma (MM), although its role in MM pathogenesis remains unclear. This study found that SLAMF3 is highly and constitutively expressed on MM cells regardless of disease stage and that SLAMF3 knockdown/knockout suppresses proliferative potential and increases drug-induced apoptosis with decreased levels of phosphorylated ERK protein in MM cells. SLAMF3-overexpressing MM cells promote aggressive myeloma behavior in comparison with cytoplasmic domain-truncated SLAMF3 (ΔSLAMF3) cells. SLAMF3 interacts directly with adaptor proteins SH2 domain-containing phosphatase 2 (SHP2) and growth factor receptor bound 2 (GRB2), which also interact with each other. SLAMF3 knockdown, knockout, ΔSLAMF3, and SHP2 inhibitor-treated MM cells decreased phosphorylated ERK protein levels. Finally, serum soluble SLAMF3 (sSLAMF3) levels were markedly increased in advanced MM. Patients with high levels of sSLAMF3 progressed to the advanced stage significantly more often and had shorter progression-free survival times than those with low levels. This study revealed that SLAMF3 molecules consistently expressed on MM cells transmit MAPK/ERK signals mediated via the complex of SHP2 and GRB2 by self-ligand interaction between MM cells and induce a high malignant potential in MM. Furthermore, high levels of serum sSLAMF3 may reflect MM disease progression and be a useful prognostic factor. IMPLICATIONS: SLAMF3 may be a new therapeutic target for immunotherapy and novel agents such as small-molecule inhibitors.


Subject(s)
MAP Kinase Signaling System , Multiple Myeloma/metabolism , Signaling Lymphocytic Activation Molecule Family/metabolism , Animals , Cell Line, Tumor , Cell Proliferation/physiology , Drug Resistance, Neoplasm , Female , Heterografts , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Phenotype , Signaling Lymphocytic Activation Molecule Family/genetics , Transfection
2.
Oncotarget ; 9(78): 34784-34793, 2018 Oct 05.
Article in English | MEDLINE | ID: mdl-30410677

ABSTRACT

The signaling lymphocytic activation molecule family (SLAMF7; also known as CS1 or CD319) is highly expressed on plasma cells from multiple myeloma (MM) as well as natural killer (NK) cells and is a well-known therapeutic target of elotuzumab. The objective of this study was to evaluate the clinical significance of serum soluble SLAMF7 (sSLAMF7) levels in patients with MM (n=103) and furthermore the impact of sSLMF7 on the antitumor activity of anti-SLAMF7 antibody. Thirty-one percent of MM patients, but not patients with monoclonal gammopathy of undetermined significance and healthy controls, had detectable levels of serum sSLAMF7, which were significantly increased in advanced MM patients. Further, MM in sSLAMF7-postive patients exhibited aggressive clinical characteristics with shorter progression-free survival times in comparison with sSLAMF7-negative patients. In responders to MM therapy, the levels of sSLAMF7 were undetectable or decreased compared with those before treatment. In addition, the anti-SLAMF7 antibody-mediated antibody-dependent cellular cytotoxicity of NK cells against MM cell lines was inhibited by recombinant SLAMF7 protein. Thus, our findings suggest that high concentrations of sSLAMF7, which could transiently suppress the therapeutic effects of elotuzumab, may be a useful indicator of disease progression in MM patients.

3.
Cancer Immunol Res ; 4(9): 779-88, 2016 09 02.
Article in English | MEDLINE | ID: mdl-27440711

ABSTRACT

B7 homolog 1 (B7-H1)-expressing myeloma cells not only inhibit myeloma-specific cytotoxic T lymphocytes (CTL), but also confer a proliferative advantage: resistance to antimyeloma chemotherapy. However, it remains unknown whether B7-H1 expressed on myeloma cells induces cellular responses associated with aggressive myeloma behaviors. To address this question, we analyzed the proliferation and drug sensitivity of B7-H1-expressing myeloma cells transfected with B7-H1-specific short-hairpin RNA or treated with programmed cell death (PD)-1-Fc-coupled beads. Knockdown of B7-H1 expression in myeloma cells significantly inhibited cell proliferation and increased apoptosis induced by the chemotherapeutic alkylating agent melphalan, with downregulation of the expression of cell cycle-related genes (CCND3 and CDK6) and antiapoptotic genes (BCL2 and MCL1). B7-H1 molecules thus contributed to myeloma cell-cycle progression and suppression of drug-induced apoptosis. B7-H1-expressing myeloma cells had a higher affinity for PD-1 than for CD80. PD-1-Fc bead-treated myeloma cells also became resistant to apoptosis that was induced by melphalan and the proteasome inhibitor bortezomib. Apoptosis resistance was associated with the PI3K/AKT pathway. Both myeloma cell drug resistance and antiapoptotic responses occurred through the PI3K/AKT signaling pathway, initiated from "reverse" stimulation of B7-H1 by PD-1. Therefore, B7-H1 itself may function as an oncogenic protein in myeloma cells. The interaction between B7-H1 on myeloma cells and PD-1 molecules not only inhibits tumor-specific CTLs but also induces drug resistance in myeloma cells through the PI3K/AKT signaling pathway. These observations provide mechanistic insights into potential immunotherapeutic benefits of blocking the B7-H1-PD-1 pathway. Cancer Immunol Res; 4(9); 779-88. ©2016 AACR.


Subject(s)
B7-H1 Antigen/metabolism , Drug Resistance, Neoplasm , Multiple Myeloma/immunology , Multiple Myeloma/metabolism , Programmed Cell Death 1 Receptor/metabolism , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , B7-1 Antigen/metabolism , B7-H1 Antigen/genetics , Cell Line, Tumor , Cell Proliferation , Drug Resistance, Neoplasm/genetics , Gene Knockdown Techniques , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Phosphatidylinositol 3-Kinases/metabolism , Programmed Cell Death 1 Receptor/genetics , Protein Binding , Proto-Oncogene Proteins c-akt , Signal Transduction
4.
Rinsho Ketsueki ; 56(7): 915-8, 2015 Jul.
Article in Japanese | MEDLINE | ID: mdl-26256931

ABSTRACT

The NCCN-International Prognostic Index (IPI) is reported to be more powerful than the former IPI for predicting survival in the rituximab era. To evaluate the NCCN-IPI in our institutions, we analyzed 188 patients with diffuse large B-cell lymphoma treated with rituximab plus CHOP or THP-COP chemotherapy. The 5-year overall survival rates of patients with low, low-intermediate, high-intermediate, and high risk were 90%, 76%, 64%, and 34%, respectively. Although there was no difference in overall survival between patients 61-75 and those >75 years of age, the NCCN-IPI is useful for classifying prognostically relevant subgroups of Japanese patients.


Subject(s)
Lymphoma, Large B-Cell, Diffuse/pathology , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Follow-Up Studies , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Male , Middle Aged , Prognosis , Retrospective Studies , Young Adult
5.
J Infect Chemother ; 21(10): 751-5, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26184853

ABSTRACT

Pseudomonas oryzihabitans (formerly Flavimonas oryzihabitans) is a glucose non-fermentative, Gram-negative bacillus which is rarely isolated from human specimens. When isolated, it is on very rare occasion as a causative pathogen of catheter-related bloodstream infection in an immunocompromised patient. Herein, we describe two hematological malignancy patients suspected to have P. oryzihabitans bacteremia. We also review cases with bacteremia due to this pathogen and its microbiological characteristics.


Subject(s)
Bacteremia , Immunocompromised Host , Pseudomonas Infections , Pseudomonas , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bacteremia/immunology , Bacteremia/microbiology , Catheter-Related Infections/microbiology , Catheters, Indwelling/adverse effects , Catheters, Indwelling/microbiology , Child, Preschool , Equipment Contamination , Humans , Lymphoma, T-Cell/complications , Lymphoma, T-Cell/drug therapy , Lymphoma, T-Cell/immunology , Male , Middle Aged , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Pseudomonas Infections/immunology , Pseudomonas Infections/microbiology
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