Research ArticleCancer

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

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Science Translational Medicine  24 Feb 2021:
Vol. 13, Issue 582, eabc4822
DOI: 10.1126/scitranslmed.abc4822

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An origin-al leukemia treatment strategy

The heterogeneity of acute myeloid leukemia (AML) has problematized understanding this cancer’s cell of origin and the role that this origin might play in the onset of treatment resistance. Zeisig et al. used cord blood and cells from patients with primary MLL-rearranged AML to determine that most MLL-AML cells are derived from either hematopoietic stem cells (HSCs) or common myeloid progenitor cells. They further showed that the ABCC3 inhibitor fidaxomicin together with doxorubicin extended survival in mouse models of treatment resistant MLL-AML derived from specifically HSCs. This work could have implications for the clinical treatment of AML with MLL rearrangement.


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.

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