Abstract 2933: Inhibition of FLT3 and AXL by gilteritinib controls systemic tumor growth in luciferase-transduced MV-4-11 acute myeloid leukemia

Abstract Mutations and amplification of the fms-like receptor tyrosine kinase FLT3 gene, such as those found in MV-4-11 cells, are common in acute myeloid leukemia (AML). Such mutations result in aberrant activation of FLT3, increased growth and survival of tumor cells, and the development of refractory forms of AML with poor patient outcomes. In addition, AXL receptor tyrosine kinase imparts chemotherapeutic resistance in AML. MV-4-11 is a human biphenotypic B myelomonocytic leukemia with t(4;11)(q21;q23) chromosomal translocation commonly found in AML patients; it possesses a homozygous in-frame tandem repeat insertion in the FLT3 allele resulting in constitutively phosphorylated FLT3. Commonly employed preclinical orthotopic models of AML are primarily evaluated based on morbidity and mortality, which provide limited real time information on tumor burden and dissemination. The purpose of this study is to develop a MV-4-11 mouse model that allows the quantification and anatomical localization of the AML cells by monitoring bioluminescent signal in live animals and to utilize this model to investigate the efficacy of a FLT3/AXL inhibitor, gilteritinib. This poster describes a) the production of luciferase-expressing human MV-4-11 (MV-4-11-luc) cells via lentiviral transduction, b) the characterization of MV-4-11-luc progression in two models of immunocompromised mice, c) the efficacy of the FLT3/AXL kinase inhibitor gilteritinib against systemic MV-4-11-luc compared with two standard AML therapies, cytarabine and cyclophosphamide and d) the development of a humanized MV-4-11 tumor bearing model in NCG mice. Bioluminescence imaging revealed dose dependent tumor growth localized to the hind limbs and peritoneal cavity, which disseminated and intensified over time. Characteristic moribundity associated with disease progression was observed in this model. By comparison, robust growth of both parental and luc-transduced MV-4-11 was also observed in the highly immunodeficient NCG mice with or without prior myeloablation. Efficacy studies in NCG mice bearing parental or luciferase-tagged MV-4-11 cells demonstrated potent anti-tumor activity using the FLT3/AXL inhibitor. Bioluminescent imaging of orthotopic MV-4-11-luc xenografts in immunocompromised mice is a quantitative and sensitive method that provides anatomical context for assessing the efficacy of AML therapeutics. Ongoing and future work is focused on a) genetic profiling of MV-4-11 tumors after treatment with gilteritinib, b) further characterization of a humanized MV-4-11 model to evaluate immune-modulating therapeutics, and c) utilizing the model to evaluate activity of cell therapies that target AML. Citation Format: Na Li, Vivek Mahajan, Lindsay Butler, Elizabeth Rainbolt, Shasta Kidder, Kay Meshaw, Diana Gietl, Susan Yeyeodu, Anya Avrutskaya, Jing Wan, Thi Bui, Chassidy Hall, David P. Harris. Inhibition of FLT3 and AXL by gilteritinib controls systemic tumor growth in luciferase-transduced MV-4-11 acute myeloid leukemia [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 2933.