Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia

• Published in: Science translational medicine 2023-03, Vol.15 (689), p.eabq8513-eabq8513
• Main Authors: Chen, Zhenhua, Zhou, Keren, Xue, Jianhuang, Small, Andrew, Xiao, Gang, Nguyen, Le Xuan Truong, Zhang, Zheng, Prince, Emily, Weng, Hengyou, Huang, Huilin, Zhao, Zhicong, Qing, Ying, Shen, Chao, Li, Wei, Han, Li, Tan, Brandon, Su, Rui, Qin, Hanjun, Li, Yangchan, Wu, Dong, Gu, Zhaohui, Ngo, Vu N, He, Xin, Chao, Jianfei, Leung, Keith, Wang, Kitty, Dong, Lei, Qin, Xi, Cai, Zhenming, Sheng, Yue, Chen, Yu, Wu, Xiwei, Zhang, Bin, Shi, Yanhong, Marcucci, Guido, Qian, Zhijian, Xu, Mingjiang, Müschen, Markus, Chen, Jianjun, Deng, Xiaolan
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; Animals; CD72 antigen; Cell survival; Cell viability; Children; Clinical trials; Demethylation; Dioxygenase; DNA-Binding Proteins - metabolism; Kinases; Leukemia; Lymphatic leukemia; Lymphocytes B; Mice; Phosphorylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Protein kinase C; Protein transport; Protein-serine/threonine kinase; Proteins; Proto-Oncogene Proteins - metabolism; Signal Transduction; Staurosporine; Therapeutic targets; Vincristine
• ISSN: 1946-6234; 1946-6242; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.abq8513

Although the overall survival rate of B cell acute lymphoblastic leukemia (B-ALL) in childhood is more than 80%, it is merely 30% in refractory/relapsed and adult patients with B-ALL. This demonstrates a need for improved therapy targeting this subgroup of B-ALL. Here, we show that the ten-eleven translocation 1 (TET1) protein, a dioxygenase involved in DNA demethylation, is overexpressed and plays a crucial oncogenic role independent of its catalytic activity in B-ALL. Consistent with its oncogenic role in B-ALL, overexpression of TET1 alone in normal precursor B cells is sufficient to transform the cells and cause B-ALL in mice within 3 to 4 months. We found that TET1 protein is stabilized and overexpressed because of its phosphorylation mediated by protein kinase C epsilon (PRKCE) and ATM serine/threonine kinase (ATM), which are also overexpressed in B-ALL. Mechanistically, TET1 recruits STAT5B to the promoters of and and promotes their transcription, which in turn promotes B-ALL development. Destabilization of TET1 protein by treatment with PKC or ATM inhibitors (staurosporine or AZD0156; both tested in clinical trials), or by pharmacological targeting of STAT5B, greatly decreases B-ALL cell viability and inhibits B-ALL progression in vitro and in vivo. The combination of AZD0156 with staurosporine or vincristine exhibits a synergistic effect on inhibition of refractory/relapsed B-ALL cell survival and leukemia progression in PDX models. Collectively, our study reveals an oncogenic role of the phosphorylated TET1 protein in B-ALL independent of its catalytic activity and highlights the therapeutic potential of targeting TET1 signaling for the treatment of refractory/relapsed B-ALL.