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

Abstract

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.

Keywords:

• JMJD1C
• lipid synthesis
• Mixed lineage leukemia rearranged acute myeloid leukemia (MLLr AML)
• small molecular inhibitors

Acknowledgments

We thank Hans Drexler and Wilhelm Dirks from Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures GmbH for the help in providing cell lines and performing cell line authentication.

Disclosure statement

All authors declare no conflict of interests.

Data availability statement

The data that support the findings of this study are available from the corresponding author, HZ, upon reasonable request.

Additional information

Funding

The research was supported by the Natural Science Foundation of Shandong Province (ZR2020KC016 and ZR2020MH117), and Weifang Science and Technology Development Plan (Grant No. 2020YQFK013).