Fung, Tsz Kan

Lynn, Claire

Mufti, Ghulam

So, Chi Wai Eric

Stanojevic, Boban

Zarowiecki, Magdalena

Zeisig, Bernd

English

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 commonmyeloid progenitors (CMPs) as two distinctive origins for human AML driven by Mixed Lineage Leukemia (MLL) gene fusions (MLL-AML). Despite LSCs from either MLLrearranged HSCs or MLL-rearranged CMPs having a mature CD34-/lo/CD38+ immunophenotype in both the humanized 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 a smallmolecule inhibitor, fidaxomicin currently used for diarrhea associated with Clostridium difficile infection, effectively re-sensitized HSC-derived MLL-AML towards 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 anti-diarrhea drug already used in the clinic

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Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment resistant MLL-rearranged leukemia

https://kclpure.kcl.ac.uk/portal/files/142095959/abc4822_CombinedPDF_v11.pdf

Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment resistant MLL-rearranged leukemia

Abstract

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