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

Zhenhua Chen, Keren Zhou, Jianhuang Xue, Andrew Small, Gang Xiao, Le Xuan Truong Nguyen, Zheng Zhang, Emily Prince, Hengyou Weng, Huilin Huang, Zhicong Zhao, Ying Qing, Chao Shen, Wei Li, Li Han, Brandon Tan, Rui Su, Hanjun Qin, Yangchan Li, Dong WuZhaohui Gu, Vu N. Ngo, Xin He, Jianfei Chao, Keith Leung, Kitty Wang, Lei Dong, Xi Qin, Zhenming Cai, Yue Sheng, Yu Chen, Xiwei Wu, Bin Zhang, Yanhong Shi, Guido Marcucci, Zhijian Qian, Mingjiang Xu, Markus Müschen, Jianjun Chen, Xiaolan Deng

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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 CD72 and JCHAIN 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 BALL 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.

Original languageEnglish (US)
Article numbereabq8513
JournalScience translational medicine
Volume15
Issue number689
DOIs
StatePublished - Mar 29 2023

ASJC Scopus subject areas

  • General Medicine

Fingerprint

Dive into the research topics of 'Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia'. Together they form a unique fingerprint.

Cite this