JMJD1C-regulated lipid synthesis contributes to the maintenance of MLL-rearranged acute myeloid leukemia

Mixed Lineage Leukemia rearranged acute myeloid leukemia (MLLr AML) predicts a poor prognosis. Histone demethylase JMJD1C is a potential druggable target of MLLr AML. However, little is known about how JMJD1C contributes to MLLr AML. Here we found that JMJD1C regulates lipid synthesis-associated genes including FADS2, SCD in MLLr AML cells. Lipid synthesis-associated protein FABP5 was identified as a specific interacting protein of JMJD1C and binds to the jumonji domain of JMJD1C. FABP5 also regulates JMJD1C mRNA and protein expression. JDI-10, a small molecular inhibitor of JMJD1C identified by us, represses MLLr AML cells, induces apoptosis, and decreases JMJD1C-regulated lipid synthesis genes. Moreover, JDI-10 mediated suppression of MLLr AML cells can be rescued by palmitic acid, oleic acid, or recombinant FABP5. In summary, we identified that JMJD1C-regulated lipid synthesis contributes to the maintenance of MLLr AML. Lipid synthesis repression may represent a new direction for the treatment of MLLr AML.

Automated summary

In this study, we investigated the role of JMJD1C in MLLr AML and found that it regulates lipid synthesis-associated genes. We identified FABP5 as an interacting protein of JMJD1C and showed that FABP5 regulates JMJD1C expression. We also developed a small molecule inhibitor of JMJD1C, JDI-10, which represses MLLr AML cells and decreases expression of JMJD1C-regulated lipid synthesis genes. These findings highlight the importance of lipid synthesis in MLLr AML and suggest that targeting lipid synthesis may be a potential therapeutic strategy.