Palmitoyltransferase ZDHHC21 regulates oxidative phosphorylation to induce AML differentiation block and chemoresistance

Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Nearly 50% of the patients who receive the most intensive treatment develop leukemia relapse. AML cells are highly dependent on mitochondrial oxidative phosphorylation (OXPHOS) for survival, especially refractory leukemia, but how OXPHOS contributes to the leukemia progression is unclear and noncytotoxic strategy to inhibit OXPHOS is lacking. Here, we demonstrate for the first time that ZDHHC21 palmitoyltransferase serves as a key regulator to regulate the OXPHOS hyperactivity in AML cells. The depletion of ZDHHC21 effectively inhibited OXPHOS activity and induced the myeloid differentiation of AML cell lines and patient-derived AML specimens. Mechanistically, ZDHHC21 specifically catalyzes the palmitoylation of mitochondrial kinase AK2 and further activates OXPHOS to arrest myeloid differentiation. Moreover, inhibition of ZDHHC21 eradicated the AML blasts and prolonged the survival of NOD/SCID mice inoculated with AML cell lines and PDX-AML cells. Besides, targeting ZDHHC21 to suppress OXPHOS markedly enhances the chemotherapy efficacy in refractory leukemia. Together, these findings not only uncover the new biological function of palmitoyltransferase ZDHHC21 in regulating AML oxidative phosphorylation, but also indicate ZDHHC21 inhibition as a potential therapy for patients with AML especially refractory leukemia.