Ablation of Wnt signaling in bone marrow stromal cells overcomes microenvironment-mediated drug resistance in acute myeloid leukemia

Author:

Palani Hamenth Kumar,Ganesan Saravanan,Balasundaram Nithya,Venkatraman Arvind,Korula Anu,Abraham Aby,George Biju,Mathews Vikram

Abstract

AbstractThe survival of leukemic cells is significantly influenced by the bone marrow microenvironment, where stromal cells play a crucial role. While there has been substantial progress in understanding the mechanisms and pathways involved in this crosstalk, limited data exist regarding the impact of leukemic cells on bone marrow stromal cells and their potential role in drug resistance. In this study, we identify that leukemic cells prime bone marrow stromal cells towards osteoblast lineage and promote drug resistance. This biased differentiation of stroma is accompanied by dysregulation of the canonical Wnt signaling pathway. Inhibition of Wnt signaling in stroma reversed the drug resistance in leukemic cells, which was further validated in leukemic mice models. This study evaluates the critical role of leukemic cells in establishing a drug-resistant niche by influencing the bone marrow stromal cells. Additionally, it highlights the potential of targeting Wnt signaling in the stroma by repurposing an anthelmintic drug to overcome the microenvironment-mediated drug resistance.

Funder

Department of Science and Technology, Ministry of Science and Technology, India

The Wellcome Trust DBT India Alliance

Department of Biotechnology, Ministry of Science and Technology, India

Publisher

Springer Science and Business Media LLC

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Targeting the bone marrow niche, moving towards leukemia eradication;Frontiers in Hematology;2024-07-22

2. Leukemic Stem Cells and Hematological Malignancies;International Journal of Molecular Sciences;2024-06-17

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