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Background: Inflammation plays a crucial role in normal and malignant hematopoiesis. Patients with acute myeloid leukemia (AML) exhibit aberrant interleukin-1β (IL-1β) signaling which results in AML progression. Previously, we have shown that IL-1β promotes the expansion of leukemic progenitors while suppresses the growth of healthy cells. To understand this paradoxical effect, we applied transcriptome analysis of IL-1β-stimulated AML versus healthy progenitors and revealed differentially expressed genes involved in inflammation, cell cycle, and chromosome organization. We identified that ASF1B (anti-silencing function1B) is one of the highly expressed genes between AML and healthy progenitors upon IL-1β stimulation. ASF1B is a histone chaperone and delivers H3-H4 histone dimers onto DNA during replication and DNA damage response. ASF1B is overexpressed in various solid tumors and associated with poor prognosis. However, the functional roles of ASF1B in hematopoiesis and inflammation-driven leukemia have not been established. Methods and Results: We observed higher ASF1B expression in AML progenitors from various AML genetic subtypes (e.g. FLT3-ITD, NPM1, and MLL-ENL) compared to healthy cells at baseline levels and upon IL-1β stimulation. ASF1B upregulation is abolished upon treatment with a p38MAPK inhibitor, suggesting that ASF1B is downstream of IL-1β/p38 signaling. To determine whether ASF1B mediates IL-1β-driven leukemic growth, we overexpressed ASF1B with MLL-ENL oncogene in a murine bone marrow transplantation model. We found that IL-1β treatment accelerated AML progression compared to the vehicle-treated group (median survival = 64 vs. 85 days, P Conclusion: We demonstrate that the ASF1B pathway is activated in response to microenvironmental cues such as IL-1β in primary AML cells. In vivo evidence using murine AML and genetic models suggests that ASF1B contributes to IL-1β-driven AML progression. Therefore, we provide rationales for using ASF1B as a surrogate marker for AML progression and a safer therapeutic target to inhibit inflammation-driven growth in various AML genetic subtypes. Citation Format: Hsin-Yun Lin, Mona Mohammadhosseini, Marina Villamor, John McClatchy, Sophia Jeng, Andrew Adey, Shannon McWeeney, Travis Stracker, Anupriya Agarwal. Disruption of a histone chaperone pathway delays inflammation-driven AML progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 531.

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.