Genome-wide CRISPR/Cas9 screening identifies determinant of panobinostat sensitivity in acute lymphoblastic leukemia

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.

Automated summary

Epigenetic alterations, such as histone acetylation, play a significant role in the malignant transformation of hematopoietic cells and the progression of diseases. Panobinostat, a pan-histone deacetylase inhibitor, has been approved for the treatment of multiple myeloma and shows promise in treating acute lymphoblastic leukemia (ALL). However, the mechanism of drug resistance in ALL is still largely unknown. Through genome-wide screening, researchers identified mitochondrial activity as the driver of panobinostat resistance in ALL. They discovered that the ectopic expression of SIRT1 activated mitochondrial activity and sensitized ALL to panobinostat treatment by activating the mitochondria-related apoptosis pathway. The transcription level of SIRT1 was also found to be significantly associated with panobinostat sensitivity in different types of tumors, suggesting it could be a potential biomarker for panobinostat response in cancers. The study suggests that patients with higher SIRT1 expression in cancer cells may benefit from panobinostat treatment, and combination therapy with SIRT1 or mitochondrial activators could overcome panobinostat resistance.