Abstract
Abstract The major therapeutic barrier in acute myeloid leukemia (AML) is chemotherapeutic resistance. Resistant cells to conventional chemotherapy - which targets DNA synthesis - are thought to be rare and enriched in quiescent leukemic stem cells. In order to develop an improved understanding of chemotherapy resistance in AML, we analyzed the response to cytarabine (AraC) and disease regrowth in a xenograft model with 13 primary AML patient specimens. After demonstrating AML engraftment, mice are treated with AraC given IP daily for 5 days as a single agent at 60 mg/kg daily, which correlates with human dosing. In all mice treated with AraC, there was a strong cytoreductive effect at 1 week post-treatment with regrowth at 2-8 weeks post-treatment, demonstrating that there is a dose response relationship in the model in terms of nadir leukemic burden and time to relapse. While in vivo AraC increases in hypoxic CD34posCD38neg phenotype, this treatment does not induce any significant changes in cell cycle progression and kills both cycling and quiescent cells in AML-engrafted mice. We also observed that AraC decreases the frequency of leukemia-initiating cells. Furthermore, transcriptomic analysis of residual leukemic cells from three patients-derived xenografts during disease progression (1-2-4 weeks post-AraC) reveals that the AraC resistance is associated with enrichment in genes involved into the apoptosis regulation, inflammatory and metabolism at early stage (1 week), and in stem cell markers with adverse prognosis at the onset of the tumor regrowth (2 week). Altogether, these results suggest a novel model for cytarabine resistance in AML. Citation Format: Jean-Emmanuel Sarry. In vivo analysis of the residual disease uncovers early and late response of cytarabine-resistant cells in human acute myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4068. doi:10.1158/1538-7445.AM2015-4068
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