Fumarate hydratase deficiency induces chronic myeloid leukemia progression

BACKGROUND: Although tyrosine kinase inhibitors (TKIs) have profoundly improved the prognosis of chronic myeloid leukemia (CML), the mechanism of the progression to blast phase (BP) is currently unclear. Our previous study indicated that CML-BP cells utilize glycolysis to proliferate and that the fumarate level is elevated in CML-BP cells. Fumarate hydratase (FH) catalyzes fumarate to malate. A functional deficiency in FH could result in fumarate accumulation. Therefore, we wanted to determine whether an FH deficiency facilitates CML progression. METHODS: FH expression in CML chronic phase (CP) and CML-BP was analyzed. In vitro, we tested whether FH expression knockdown induces glycolysis and increases K562 cell invasiveness. DNA damage repair after FH expression knockdown was also tested. RESULTS: Our findings showed that CML-BP patients had lower FH expression than CML-CP patients (P=0.025). Knocking down FH expression enhanced the invasiveness of K562 cells through HIF-1α-induced glycolysis. DNA damage repair was impaired after FH expression knockdown. CONCLUSIONS: Our findings suggested that reduced FH function may facilitate disease progression in CML through the combined effects of an elevated glycolysis level and a decreased DNA repair ability.