Targeting SIRT6 epigenetically restrains neutrophil hyperplasia and enhances chemotherapeutic efficacy.

Myeloproliferative neoplasms (MPNs) are a group of hematologic malignancies for which current treatment options remain limited, underscoring the urgent need to explore novel therapeutic targets and intervention strategies. Through a high-throughput screen of an epigenetic compound library, we identified the SIRT6 allosteric agonist MDL-800 as a potent suppressor of neutrophil hyperplasia. We established an endogenous sirt6-mutant zebrafish model that develops a myeloproliferative neoplasm (MPN)-like phenotype, with a 64% incidence in adult zebrafish. Mechanistically, Sirt6 was found to regulate neutrophil proliferation in vivo and in vitro by deacetylating histone H3K9 at the c-myb promoter. Sirt6 deficiency led to aberrant proliferation of neutrophils and hematopoietic stem/progenitor cells, whereas Sirt6 overexpression significantly alleviated neutrophil hyperplasia and MPN-related symptoms. Furthermore, the SIRT6 activator MDL-800 enhanced the efficacy of imatinib and reduced neutrophil proliferation in a zebrafish leukemia model. In xenograft mouse models, the combination of MDL-800 and imatinib significantly inhibited leukemia progression and restored drug sensitivity in imatinib-resistant cases. This study establishes the Sirt6-c-Myb axis as a core epigenetic pathway for myeloid homeostasis, providing a novel strategy for simultaneously suppressing neutrophil hyperplasia and enhancing chemotherapeutic efficacy in hematologic malignancies.