Abstract
AML1-ETO fusion protein (AE) is generated by t(8;21)(q22;q22) chromosomal translocation, which is one of the most frequently observed structural abnormalities in acute myeloid leukemia (AML) and displays a pivotal role in leukemogenesis. The histone acetyltransferase p300 promotes self-renewal of leukemia cells by acetylating AE and facilitating its downstream gene expression as a transcriptional coactivator, suggesting that p300 may be a potential therapeutic target for AE-positive AML. However, the effects of p300 inhibitors on leukemia cells and the underlying mechanisms have not been extensively investigated. In the current study, we analyzed the anti-leukemia effects of C646, a selective and competitive p300 inhibitor, on AML cells. Results showed that C646 inhibited cellular proliferation, reduced colony formation, evoked partial cell cycle arrest in G1 phase, and induced apoptosis in AE-positive AML cell lines and primary blasts isolated from leukemic mice and AML patients. Nevertheless, no significant inhibitory effects were observed in granulocyte colony-stimulating factor-mobilized normal peripheral blood stem cells. Notably, AE-positive AML cells were more sensitive to lower C646 doses than AE-negative ones. And C646-induced growth inhibition on AE-positive AML cells was associated with reduced global histone H3 acetylation and declined c-kit and bcl-2 levels. Therefore, C646 may be a potential candidate for treating AE-positive AML.
Highlights
Leukemogenesis involves a variety of recurrent chromosomal abnormalities. t(8;21)(q22;q22) translocation is the most common chromosomal aberration identified in acute myeloid leukemia (AML), which occurs in 40% of patients with French-American-British (FAB) M2 subtype and constitutes 12% of all newly-diagnosed cases [1]
We found that C646 inhibited cellular proliferation, reduced colony formation, evoked partial cell cycle arrest in G1 phase, and induced apoptosis in a fusion protein (AE)-positive AML cells, while no significant inhibitory effects were observed in normal peripheral blood stem cells (PBSCs)
The C646-induced cleavage of caspases3, 8, and 9 was partially blocked by pretreatment with Q-VD-OPH (Figure 1E). These results indicated that the C646-evoked growth inhibition of AE-positive AML cell lines was associated with cell cycle arrest and induction of apoptosis
Summary
Leukemogenesis involves a variety of recurrent chromosomal abnormalities. t(8;21)(q22;q22) translocation is the most common chromosomal aberration identified in AML, which occurs in 40% of patients with French-American-British (FAB) M2 subtype and constitutes 12% of all newly-diagnosed cases [1]. T(8;21)(q22;q22) translocation is the most common chromosomal aberration identified in AML, which occurs in 40% of patients with French-American-British (FAB) M2 subtype and constitutes 12% of all newly-diagnosed cases [1]. This chromosomal translocation results in expression of AML1-ETO fusion oncogene. It has been reported that AE binds the transcriptional coactivator p300 through its NHR1 domain, allowing AE and p300 to colocalize at the regulatory regions of various genes up-regulated by AE and involved in self-renewal of hematopoietic stem/progenitor cells (e.g. Id1, p21 and Egr1) [5]. P300 may be a potential therapeutic target for AE-positive leukemia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
