Modulators of histone demethylase JMJD1C selectively target leukemic stem cells

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Leukemic stem cells (LSCs) drive acute myeloid leukemia (AML) development.
• Targeting LSC-specific drivers offers a promising therapeutic strategy for AML.
• Histone lysine demethylase JMJD1C is a potential therapeutic target in certain leukemias.

Purpose of the Study:

• To identify and characterize novel small molecule inhibitors of JMJD1C.
• To evaluate the selective efficacy of these inhibitors against LSCs.
• To explore the therapeutic potential of JMJD1C modulators in AML.

Main Methods:

• Surface plasmon resonance (SPR) for binding analysis.
• Cell proliferation assays (liquid and semi-solid culture).
• Molecular docking and gene expression analysis (HOXA9).

Main Results:

• JDM-7 binds to JMJD1C and JMJD1B, downregulating LSC self-renewal gene HOXA9.
• JDM-7 selectively inhibits leukemia cell colony formation at low doses.
• Tadalafil also binds JMJD1C and exhibits similar selective anti-leukemic effects.
• Neither compound significantly impacted erythroid progenitor or umbilical cord blood cell proliferation.

Conclusions:

• JDM-7 and tadalafil are identified as potent JMJD1C modulators.
• These compounds demonstrate selective inhibition of LSC growth.
• JDM-7 and tadalafil represent potential novel therapeutics for AML.