Epigenetic alterations, including histone acetylation, contribute to the malignant transformation of hematopoietic cells and disease progression, as well as the emergence of chemotherapy resistance. Targeting histone acetylation provides new strategies for the treatment of cancers. As a pan-histone deacetylase inhibitor, panobinostat has been approved by the US Food and Drug Administration for the treatment of multiple myeloma and has shown promising antileukemia effects in acute lymphoblastic leukemia (ALL). However, the underlying drug resistance mechanism in ALL remains largely unknown. Using genome-wide Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas)9 (CRISPR/Cas9) screening, we identified mitochondrial activity as the driver of panobinostat resistance in ALL. Mechanistically, ectopic SIRT1 expression activated mitochondrial activity and sensitized ALL to panobinostat through activating mitochondria-related apoptosis pathway. Meanwhile, the transcription level of SIRT1 was significantly associated with panobinostat sensitivity across diverse tumor types and thus could be a potential biomarker of panobinostat response in cancers. Our data suggest that patients with higher SIRT1 expression in cancer cells might benefit from panobinostat treatment, supporting the implementation of combinatorial therapy with SIRT1 or mitochondrial activators to overcome panobinostat resistance.
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