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Activation of the PI3K/AKT/mTOR pathway in diffuse large B cell lymphoma: clinical significance and inhibitory effect of rituximab

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Abstract

Diffuse large B cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma and accounts for approximately 30 % of newly diagnosed lymphoid neoplasms in Western countries, and 40–50 % in China. A better understanding of the biology of DLBCL is needed for the development of potential therapeutic agents that target specific intracellular pathways. In this study, expression of the important components of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway and their clinical significance were investigated in 73 DLBCL cases. The effect of rituximab alone or combined with the PI3K/AKT/mTOR pathway inhibitor rapamycin was further evaluated in the DLBCL cell lines. A total of 73 patients were identified, including 45 men and 28 women aged 18 to 78 years (median age 50 years). Of these patients, p-AKT was positive in 40 cases (54.8 %), p-p70S6K in 34 cases (46.6 %), and p-4E-BP1 in 33 cases (45.2 %). Activation of the PI3K/AKT/mTOR pathway was related to poor disease outcome in DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) but not in those treated with rituximab-CHOP. Rituximab combined with rapamycin synergically downregulated the PI3K/AKT/mTOR signaling pathway. Western blot analysis revealed a baseline activation status of the PI3K/AKT/mTOR pathway in DLBCL cell lines, with high levels of p-AKT, p-mTOR, in addition to downstream molecules p-p70S6K and p-4E-BP1. The results indicate that the PI3K/AKT/mTOR pathway is a potentially important signaling route and an unfavorable prognostic factor for DLBCL. Patients with PI3K/AKT/mTOR activation experience a more rapidly deteriorating clinical course with poor treatment response and decreased survival time. Addition of rituximab could downregulate PI3K/AKT/mTOR activation, reversing its negative effect on chemotherapy-treated patients. In addition, our results indicate that the combination of rituximab and inhibition of the activated PI3K/AKT/mTOR pathway could be a promising target for DLBCL therapeutic intervention in the future.

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Acknowledgments

This work was supported in part by the Shanghai Commission of Science and Technology (grants 44107025 and 05DZ19317), the National Natural Science Foundation of China (grants 30570777 and 30750335), the Chinese National High Tech Program (grant 863:2006AA02A301), the Shanghai Commission of Science and Technology (grants 08410708800 and 11140901200), and the Program for Outstanding Young Teachers in Universities of Shanghai (JDY09084).

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All authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Zi-Zhen Xu

  2. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Zu-Guang Xia

  3. Department of Hematology, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Zi-Zhen Xu, Ai-Hua Wang, Wen-Fang Wang, Zhi-Yin Liu, Li-Yun Chen & Jun-Min Li

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  1. Zi-Zhen Xu
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  2. Zu-Guang Xia
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Correspondence to Jun-Min Li.

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Xu, ZZ., Xia, ZG., Wang, AH. et al. Activation of the PI3K/AKT/mTOR pathway in diffuse large B cell lymphoma: clinical significance and inhibitory effect of rituximab. Ann Hematol 92, 1351–1358 (2013). https://doi.org/10.1007/s00277-013-1770-9

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  • DOI: https://doi.org/10.1007/s00277-013-1770-9

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