TET1 promotes the initiation and progression of precursor B-cell malignancies independent of catalytic activity and serves as a therapeutic target

Although the overall survival rate of B cell lymphoblastic leukemia (B-ALL) in childhood is over 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 3-4 months. We found that TET1 protein is stabilized and overexpressed due to its phosphorylation mediated by protein kinase C epsilon (PRKCE) and 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 inhibitors in clinical trials Staurosporine or AZD0156, 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.  

The uploaded files contain all computational codes for the data analysis.