HDAC8 inhibition targets STAT3–MYC axis and synergizes with Venetoclax in KMT2A-rearranged acute myeloid leukemia

KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) is an aggressive AML subtype characterized by 11q23 chromosomal rearrangements involving KMT2A gene and clinically associated with poor prognosis. Herein, we show that HDAC8 is upregulated in KMT2A-r AML and high HDAC8 is associated with poor overall survival in KMT2A-r AML patients. Using a KMT2A::MLLT3 mouse model, we demonstrate that both genetic knockout and pharmacological inhibition of HDAC8 significantly delayed leukemia progression, prolonged survival and reduced disease recurrence. Mechanistically, HDAC8 inhibition downregulates STAT3-MYC axis independent of TP53 status across AML genetic subtypes. Biochemical assays revealed that HDAC8 binds directly to STAT3, promoting its deacetylation and stabilization, while HDAC8-selective inhibitor (HDAC8i) treatment results in increased STAT3 acetylation and subsequent STAT3 degradation which in turn downregulates MYC. Given that STAT3-MYC signaling promotes cell survival and Venetoclax resistance, we show that HDAC8i exhibits synergistic anti-leukemia activity with Venetoclax in primary AML cells regardless of TP53 status. Combination of HDAC8i and Venetoclax synergistically reduced leukemia burden and significantly prolonged survival in both KMT2A::MLLT3 AML and patient-derived xenograft models. This study highlights the regulatory function of HDAC8 on STAT3-MYC and provides the proof-of-principle for targeting HDAC8 in combination with Venetoclax for the treatment of KMT2A-r AML.