TY - JOUR
T1 - SPIB is a novel prognostic factor in diffuse large B-cell lymphoma that mediates apoptosis via the PI3K-AKT pathway
AU - Takagi, Yusuke
AU - Shimada, Kazuyuki
AU - Shimada, Satoko
AU - Sakamoto, Akihiko
AU - Naoe, Tomoki
AU - Nakamura, Shigeo
AU - Hayakawa, Fumihiko
AU - Tomita, Akihiro
AU - Kiyoi, Hitoshi
N1 - Funding Information:
We would like to thank Mr Kuniyoshi Kitou, Ms Kazuko Matsuba, Ms Yuko Katayama and Mr Yoshiaki Inagaki (Nagoya University) for IHC work, Ms Yoko Matsuyama, Ms Chika Wakamatsu, Ms Manami Kira, Ms Rie Kojima, Ms Yukie Konishi, Ms Yuko Kojima and Ms Emi Kohno (Nagoya University) for assistance with laboratory work, Dr W. S. Pear (University of Pennsylvania) for providing the MIGR1 vector, and Dr Kunihiko Takeyama (Dana Farber Cancer Institute) for providing the SU-DHL4 cell line. This work was supported by the Program to Disseminate Tenure Tracking System, MEXT, Japan, by a JSPS Grant-in-Aid for Young Scientists (B) 26860724 and by the Kanae Foundation for the Promotion of Medical Science grant to K.S., and by a JSPS Grant-in-Aid for Scientific Research (B) 25293218 grant to T.N.
Publisher Copyright:
© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
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U2 - 10.1111/cas.13001
DO - 10.1111/cas.13001
M3 - Article
C2 - 27348272
AN - SCOPUS:84987620760
VL - 107
SP - 1270
EP - 1280
JO - Cancer Science
JF - Cancer Science
SN - 1347-9032
IS - 9
ER -