Abstract 531: Disruption of a histone chaperone pathway delays inflammation-driven AML progression

Abstract

Abstract 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<0.05), and this effect was phenocopied by overexpression of ASF1B (median survival = 62 vs. 85 days, P<0.05). Conversely, both heterozygous and complete ASF1B deletion in the MLL-ENL AML model delayed the leukemia progression compared to wildtype mice (median survival = 67 and 68 days vs. 62 days, P<0.01). Additionally, ASF1B deletion attenuated IL-1β-mediated AML progression compared to wildtype controls (median survival = 63 vs. 47 days, P<0.01). Bone marrow and spleen cells harvested from the moribund mice exhibited myeloid phenotypes, indicating that observed survival differences are due to the impact of ASF1B deficiency on leukemic cell growth. Interestingly, immunophenotyping of Asf1b-deficient mice using flow cytometry suggested that ASF1B is dispensable for normal hematopoiesis. 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.