title: SPIB is a novel prognostic factor in diffuse large B-cell lymphoma that mediates apoptosis via the PI3K-AKT pathway.
abstract: Although the clinical outcomes of diffuse large B-cell lymphoma (DLBCL) have improved in the immunochemotherapy era, approximately one-third of patients develop intractable disease. To improve clinical outcomes for these patients, it is important to identify those with poor prognosis prior to initial treatment in order to select optimal therapies. Here, we investigated the clinical and biological significance of SPIB, an Ets family transcription factor linked to lymphomagenesis, in DLBCL. We classified 134 DLBCL patients into SPIB negative (n = 108) or SPIB positive (n = 26) groups by immunohistochemical staining. SPIB positive patients had a significantly worse treatment response and poor prognosis compared with SPIB negative patients. Multivariate analysis for patient survival indicated that SPIB expression was an independent poor prognostic factor for both progression free survival (PFS) and overall survival (OS) (PFS, hazard ratio [HR] 2.65, 95% confidence interval [CI] 1.31-5.33, P = 0.006; OS, HR 3.56, 95% CI 1.43-8.91, P = 0.007). Subsequent analyses of the roles of SPIB expression in DLBCL pathogenesis revealed that SPIB expression in lymphoma cells resulted in resistance to the BH3-mimetic ABT-263 and contributed to apoptosis resistance via the PI3K-AKT pathway. The inhibition of AKT phosphorylation re-sensitized SPIB expressing lymphoma cells to ABT-263-induced cell death. Together, our data indicate that SPIB expression is a clinically novel poor prognostic factor in DLBCL that contributes to treatment resistance, at least in part, through an anti-apoptotic mechanism.
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takagi
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan. kshimada@med.nagoya-u.ac.jp.|Institute for Advanced Research, Nagoya University, Nagoya, Japan. kshimada@med.nagoya-u.ac.jp.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Shimada
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Department of Hematology, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
authors.affiliation: Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hayakawa
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tomita
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C076877:SPIB protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Apoptosis; PI3K-AKT pathway; SPIB; diffuse large B-cell lymphoma; prognostic factor