Therapeutic Inhibition of HDAC10 Confers Therapeutic Vulnerability on Leukemia Stem Cell–like Cells Resistant to the Venetoclax + Azacitidine Regimen in Acute Myeloid Leukemia

ABSTRACT: Although the venetoclax + azacitidine (VA) combination regimen is highly effective for elderly and other acute myeloid leukemia (AML) patients unsuitable for intensive chemotherapy (IC), the treatment is limited by prolonged myelosuppression and eventual relapse and resistance. Through high-throughput sequencing, we found that histone deacetylase 10 (HDAC10) was aberrantly upregulated in VA-resistant leukemia stem cell (LSC)–like cells. Overexpression (OE) of HDAC10 in LSC-like cells reduced their sensitivity to VA treatment. Both short-hairpin ribonucleic acid (shRNA)–mediated knockdown (KD) and pharmacological inhibition of HDAC10 significantly reversed LSC resistance by enhancing F-box/WD repeat–containing protein 7 (FBXW7) acetylation and upregulating FBXW7 protein levels, which in turn suppressed induced myeloid leukemia cell differentiation protein (MCL-1) expression and overcame LSC-driven resistance to the VA regimen. Furthermore, elevated FBXW7 enhanced ubiquitination of HDAC10 at the lysine 355 (Lys355) site, leading to further HDAC10 degradation. Functionally, administration of chidamide into VA-resistant patient-derived tumor xenograft (PDX) models mitigated leukemia blasts and significantly prolonged survival in these models. Finally, in 13 high-risk VA-refractory AML patients, adding chidamide to venetoclax + azacitidine (VAC) yielded a composite complete-remission (CR) rate of 38.5% and a 1‑year overall-survival (OS) rate of 52.7% with manageable toxicity, demonstrating potential benefits for patients with relapsed/refractory (R/R) AML. In summary, this study identified a new vulnerable therapeutic target in the treatment of resistant acute R/R AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE349042 | GEO | 2026/10/04

REPOSITORIES: GEO