Chemoresistance remains the major challenge for successful treatment of acute myeloid leukemia (AML). Although recent mouse studies suggest that treatment response of genetically and immunophenotypically indistinguishable AML can be influenced by their different cells of origin, corresponding evidence in human disease is still largely lacking. By combining prospective disease modeling using highly purified human hematopoietic stem or progenitor cells with retrospective deconvolution study of leukemia stem cells (LSCs) from primary patient samples, we identified human hematopoietic stem cells (HSCs) and common myeloid progenitors (CMPs) as two distinctive origins of human AML driven by Mixed Lineage Leukemia (MLL) gene fusions (MLL-AML). Despite LSCs from either MLL-rearranged HSCs or MLL-rearranged CMPs having a mature CD34-/lo/CD38+ immunophenotype in both a humanized mouse model and primary patient samples, the resulting AML cells exhibited contrasting responses to chemotherapy. HSC-derived MLL-AML was highly resistant to chemotherapy and expressed elevated amounts of the multispecific anion transporter ABCC3. Inhibition of ABCC3 by shRNA-mediated knockdown or with small-molecule inhibitor fidaxomicin, currently used for diarrhea associated with Clostridium difficile infection, effectively resensitized HSC-derived MLL-AML toward standard chemotherapeutic drugs. This study not only functionally established two distinctive origins of human LSCs for MLL-AML and their role in mediating chemoresistance but also identified a potential therapeutic avenue for stem cell-associated treatment resistance by repurposing a well-tolerated antidiarrhea drug already used in the clinic.

CLIP Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol 150 06 Prague 5 Czech Republic

Computational Regulatory Genomics MRC London Institute of Medical Sciences London W12 0NN UK

Department of Haematological Medicine King's College Hospital London SE5 9RS UK

Department of Medicine The University of Hong Kong Pokfulam Road HKSAR China

Department of Medicine University Hospital 01307 Dresden Germany

Division of Pediatric Hematology Oncology Department of Pediatrics Penn State Cancer Institute Pennsylvania State University College of Medicine Hershey PA 17033 USA

Institute of Clinical Sciences Faculty of Medicine Imperial College London London W12 0NN UK

Laboratory for Radiobiology and Molecular Genetics Vinca Institute of Nuclear Science University of Belgrade 11000 Belgrade Serbia

Leukaemia and Stem Cell Biology Group School of Cancer and Pharmaceutical Sciences King's College London SE5 9NU UK

Sars International Centre for Marine Molecular Biology University of Bergen N 5008 Bergen Norway

Citace poskytuje Crossref.org