Leukemic transformation and the development of leukemic stem cells (LSCs) are regulated by multiple mechanisms, including altered metabolic state and epigenetic processes. JMJD1C, a Jumonji C-Domain containing histone demethylase, has been reported to interact with the oncogenic transcription factor HOXA9. This interaction modulates the downstream genes essential for the function and growth of LSCs in acute myeloid leukaemia (AML). Our research uncovers a novel role of JMJD1C in HOXA9-dependent transformation, and demonstrates that JMJD1C function is largely context-dependent in cancer.
Our results show that enforced expression of JMJD1C in HOXA9-driven-pre LSC increased in vivo cell proliferation and tumorigenicity via modulation of cellular metabolism. JMJD1C expression upregulated a specific metabolic program, which fulfils the bioenergetic requirements needed for leukemogenesis. Pharmacological inhibition of specific metabolic pathways caused ATP depletion and induction of cell death in murine LSCs and several human leukaemia cell lines, which co-express endogenous JMJD1C and HOXA9. However, enforced JMJD1C expression prevented metabolic inhibition-induced decrease in ATP production conferred protection against metabolic impairment in HOXA9-dependent leukemic cells.
In conclusion, our findings report a novel role for oncoprotein JMJD1C in the regulation of cancer metabolism and identify a unique metabolic mechanism which can be explored therapeutically.