Modulators of histone demethylase JMJD1C selectively target leukemic stem cells.

ABSTRACT: Leukemic stem cells (LSCs) are a very rare cell population that result in the development of acute myeloid leukemia (AML). The selective targeting of drivers in LSCs with small molecule inhibitors holds promise for treatment of AML. Recently, we reported the identification of inhibitors of the histone lysine demethylase JMJD1C that preferentially kill MLL rearranged acute leukemia cells. Here, we report the identification of JMJD1C Jumomji domain Modulator 7 (JDM-7). Surface plasmon resonance (SPR) analysis showed that JDM-7 binds to JMJD1C and its family homolog JMJD1B. JDM-7 did not significantly suppress cell proliferation in liquid cell culture at higher doses, but led to a significant decrease in semi-solid colony formation experiments at lower concentrations. Moreover, low doses of JDM-7 did not suppress the proliferation of erythroid progenitor cells. We identified that JDM-7 downregulates the LSC self-renewal gene HOXA9 in leukemia cells. We further found that the structure of JDM-7 is similar to that of Tadalafil, an FDA approved drug. Molecular docking and surface plasmon resonance (SPR) analysis showed that Tadalafil binds to JMJD1C. Moreover, like JDM-7, Tadalafil suppressed colony formation of leukemia cells in semi-solid cell culture at a concentration that did not affect primary umbilical cord blood cells. In summary, we have identified JDM-7 and Tadalafil as potential JMJD1C modulators that selectively inhibit the growth of LSCs.

SUBMITTER: Yang Y 

PROVIDER: S-EPMC7780120 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature