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Genetic heterogeneity remains an ongoing challenge in treating acute myeloid leukemia (AML). Identifying microenvironment-driven pathways that are active across AML genetic subtypes should allow the development of broadly effective therapies. We have shown that AML microenvironment is rich in proinflammatory cytokine interleukin-1β (IL-1β) and promotes AML progression. The transcriptome analysis revealed that ASF1B (anti-silencing function1B), a histone chaperone, is one of the most differentially expressed genes in AML progenitors as compared to normal cells upon IL-1β stimulation. The functional roles of ASF1B in hematopoiesis and leukemia remain elusive. We identified that IL-1β upregulates ASF1B in various genetic subtypes of AML at both mRNA and protein levels. Upon shRNA-mediated ASF1B depletion, AML cells exhibited reduced cell viability, inhibited growth, cell cycle arrest, and impaired colony formation ability. In vivo xenograft model showed 80% reduction in leukemic burden and spleen size following ASF1B silencing. Using a MLL-ENL murine bone marrow transplantation model, we found that ASF1B overexpression alone shortened survival (p = 0.02) of MLL-ENL leukemic mice to the same extent as IL-1β-treated recipients versus vehicle-treated group (p = 0.03), suggesting that high ASF1B levels mimic IL-1β-mediated growth effects in AML. In a complementary study, both heterozygous and complete deletion of ASF1B extended survival of mice (p In summary, we demonstrate that elevated ASF1B expression promotes disease progression in AML. We also provide in vitro and in vivo evidence that ASF1B plays a critical role in potentiating IL-1β-dependent AML growth. Therefore, ASF1B can serve as a novel route of therapeutic strategy to suppress microenvironmental-driven growth in various AML genetic subtypes.