The JAK2 inhibitor TG101209 exhibits anti-tumor and chemotherapeutic sensitizing effects on Burkitt lymphoma cells by inhibiting the JAK2/STAT3/c-MYB signaling axis

Yang Zhang,Ji Li,Zhao Cheng,Xiang Xiao,Zhihua Wang,Sufang Liu,Cunhong Hu,Haiying Zhong,Guangsen Zhang

doi:10.1038/s41420-021-00655-1

Abstract

Constitutive activation of JAK2/STAT3 is a major oncogenic signaling event involved in the development of Burkitt lymphoma (BL). In the present study, we investigated the antilymphoma activity of TG101209, a specific JAK2 inhibitor, on EBV-positive and EBV-negative Burkitt lymphoma cell lines and primary BL cells. The results showed that TG101209 had a significant antilymphoma effect by inhibiting BL cell growth and inducing apoptosis along with cell differentiation toward mature B cells in vitro. We also found that TG101209 displayed significant synergistic action and a sensitizing effect on the anti-Burkitt lymphoma activity of doxorubicin. In vivo experiments indicated that TG101209 could suppress tumor growth and prolong the overall survival of BL cell-bearing mice. The mechanistic study indicated that TG101209, by suppressing the JAK2/STAT3/c-MYB signaling axis and crosstalk between the downstream signaling pathways, plays an antilymphoma role. These data suggested that TG101209 may be a promising agent or alternative choice for the treatment of BL.

Highlights

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that occurs in children and adults and is largely curable with the use of intensive and toxic chemotherapy
To confirm the inhibitory activity of TG101209 on the constitutive activation of JAK2/STAT3 signaling in BL cells, we detected the phosphorylation status of JAK2/STAT3 in TG101209-treated cells
While phosphorylated Y705 is generally believed to be essential for STAT3’s transcriptional activity; we have detected the pY705 of STAT3 to reflect the activity of STAT3.The results showed that TG101209 (6 μM) might further inhibit JAK2 and STAT3 phosphorylation at the half-hour time point in Raji cells or Ramos cells

Summary

Introduction

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that occurs in children and adults and is largely curable with the use of intensive and toxic chemotherapy. BL is often involved in the maxillofacial and abdominal organs, central nervous system and other extranodal organs or in the form of Burkitt leukemia variant, suggesting a higher tumor burden, a fast-growing manner and predisposition to the risk of chemotherapy-related tumor lysis syndrome [3]. The application of short-term intensive chemotherapy combined with the anti-CD20 antibody rituximab has greatly improved the rate of complete remission and overall survival of BL [4], the toxic response or age limitation of chemotherapy is still the main barrier for BL therapy. It is urgent and important to find new treatment methods to improve the treatment of Burkitt lymphoma

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Conclusion