Abstract 3783: Niche driven inflammatory regulation in the pathogenesis and treatment of myeloid malignancies

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are blood cancers with limited treatment options and poor outcomes. The bone marrow (BM) microenvironment significantly influences disease progression; conversely, MDS/AML remodels the niche to its advantage. Indeed, AML cells utilize the Kynurenine-HTR1B-SAA1 axis to reshape the BM niche, creating a pro-inflammatory environment that supports leukemic stem cell (LSC) proliferation. Given these insights, this study aims to investigate the role of SAA1 (Serum amyloid A1) in the progression of MDS and AML and explore potential therapeutic strategies to inhibit its activity. The quantification of bone marrow plasma levels of SAA1 in MDS and AML patients showed a strong correlation with disease severity and progression. Survival analysis revealed that SAA1 levels >4.0 µg/mL were associated with significantly poorer outcomes across all IPSS-R categories, including Very Low/Low-risk groups, highlighting its prognostic value. Functional in vitro and in vivo assays demonstrated that SAA1 selectively stimulates the proliferation of leukemic cells while sparing healthy hematopoietic stem cells (HSCs). Similarly, SAA1 enhanced the clonogenic potential of ASXL1- and TET2-mutant cells, suggesting its role in promoting stem-like properties in genetically altered hematopoietic cells, driving malignancy. Single-cell RNAseq analysis revealed that treatment of primary AML cells with SAA1 induces upregulation of pro-inflammatory cytokines, including IFN-ϒ, IL-6, TNF-α, and IL-1β, chemokines CXCL1 and CXCL8, and activates NFκB signaling, pathways promoting expansion of malignant and pre-malignant clones. In addition, it upregulates the expression of several genes associated with chemoresistance. A mouse monoclonal antibody was developed against SAA1 - 18A3. This antibody significantly inhibited the proliferation of leukemic cells and reduced NFκB activity in vitro. EdU incorporation assays demonstrated that SAA1 selectively promotes the proliferation of malignant cells in both leukemic and solid tumor lines such as T-ALL, B-ALL and pancreatic. The monoclonal antibody suppressed this effect. An in vivo study in an MLL-AF9 AML mouse model validated the therapeutic potential of anti-SAA1 antibody. Mice treated with the antibody showed reduced leukemic burden, as evidenced by bioluminescence imaging, and improved survival compared to untreated controls. Treated mice also maintained body weight and exhibited reduced disease progression, demonstrating the efficacy of the monoclonal antibody in mitigating leukemic proliferation. These findings establish SAA1 as a critical driver of leukemic progression and a valuable prognostic biomarker. The development of SAA1-neutralizing antibodies offers a promising therapeutic strategy for SAA1-targeted therapies to disrupt the inflammatory niche and improve outcomes in MDS and AML. Citation Format: Pallavi Budgude, Brian Chernak, Marta Galan Diez, Abdullah M. Ali, Ziwei Chen, Raul Rabadan, Martin Caroll, Azra Raza, Stavroula Kousteni. Niche driven inflammatory regulation in the pathogenesis and treatment of myeloid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3783.