Abstract
Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, a structural analog of NSC-370284, exhibited a more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three fold. NSC-370284 and UC-514321 both directly target STAT3/5, transcriptional activators of TET1, and thus repress TET1 expression. They also exhibit strong synergistic effects with standard chemotherapy. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.
Highlights
In contrast to the repression and tumor-suppressor role of TET2 observed in hematopoietic malignancies[14,15,16,17], we recently showed that Ten-eleven translocation 1 (TET1) was significantly upregulated in MLL-rearranged Acute myeloid leukemia (AML) and played an essential oncogenic role in the development of MLL-fusioninduced leukemia[18,19]
Our results showed that NSC-311068 (6-(1-Pyrrolidinyl(3,4,5-trimethoxyphenyl)methyl)-1,3-benzodioxol-5-ol; C21H25NO6) and NSC-370284 (Pyrimidine, 4-[(2,4-dinitrophenyl)thio]-; C10H6N4O4S) exhibited the most significant effects in inhibiting cell viability of all four TET1-high AML cell lines, whereas showing no significant inhibition on viability of NB4/t(15;17) AML cells, a control cell line with very low level of TET1 expression (Fig. 1a, b)
While knockout of Tet[1] expression shows only very minor effects on normal development including hematopoiesis[21], our recent studies demonstrated that TET1 plays a critical oncogenic role in AML through promoting expression of oncogenic targets (e.g., HOXA9, MEIS1, PBX3, etc.) and repressing expression of tumorsuppressor targets[18,19,46]
Summary
Through a series of in vitro drug screening and in vivo preclinical animal model studies, we identified chemical compounds NSC-370284 and UC-514321 (a more effective analog of NSC-370284) as potent inhibitors that significantly and selectively suppress the viability of AML cells with high level of TET1 expression (i.e., TET1-high AML cells), and dramatically repress the progression of TET1-high AML in mice. These compounds directly bind STAT3/5 as STAT inhibitors and thereby suppress TET1 transcription and TET1 signaling, leading to potent anti-leukemic effects
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