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Background Acute myeloid leukemia (AML) remains a highly aggressive hematologic malignancy with poor survival outcomes. Its genetic heterogeneity and dynamic clonal architecture pose major challenges for therapeutic development and predictive modeling. Conventional AML models—including cell lines, syngeneic mouse systems, or immunodeficient mice lacking human immune components—fail to replicate the tumor-immune dynamics critical for evaluating immune-based therapies. Additionally, repeated passaging of AML samples can erode clonal diversity, limiting translational relevance.Methods To overcome these limitations, Champions Oncology and Taconic Biosciences developed a humanized in vivo AML platform using NOG-EXL mice, which express human IL-3 and GM-CSF to support human hematopoiesis. Mice were first engrafted with human CD34 + cord blood-derived hematopoietic stem cells (HSCs) to establish multilineage immune reconstitution. After immune system establishment, mice were co-engrafted with primary, never-passaged AML patient-derived xenografts (PDXs) selected from Champions’ proprietary AML biobank. Each PDX is molecularly characterized via RNA-seq, proteomics, and clinical annotation. Longitudinal monitoring was performed via flow cytometry in peripheral blood and bone marrow.Results CD34 + HSC-engrafted NOG-EXL mice demonstrated robust human immune cell reconstitution, including myeloid and lymphoid lineages. Subsequent AML PDX engraftment yielded consistent leukemia progression within an immune-engaged setting. A custom multiparametric flow cytometry panel enabled simultaneous identification of human immune subsets and leukemic populations, including blasts, progenitors, and monoblasts. This dual-engraftment system allowed functional assessment of tumor-immune interactions and therapy response in a biologically relevant context.Conclusions This humanized AML model represents a powerful translational platform for evaluating immunotherapies—including monoclonal antibodies, bispecific T-cell engagers, and CAR-T cell therapies—in a system that preserves both human immune functionality and native tumor complexity. By addressing key limitations of conventional models, Champions Oncology’s approach sets a new standard for preclinical leukemia modeling and supports the rational development of immune-targeted treatments for AML.