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

TitleFunctional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia
Authors
Issue Date2021
PublisherAmerican Association for the Advancement of Science. The Journal's web site is located at http://www.sciencemag.org/marketing/stm/
Citation
Science Translational Medicine, 2021, v. 13 n. 582, p. article no. eabc4822 How to Cite?
AbstractChemoresistance 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.
Persistent Identifierhttp://hdl.handle.net/10722/307902
ISSN
2023 Impact Factor: 15.8
2023 SCImago Journal Rankings: 6.510
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZeisig, BB-
dc.contributor.authorFung, TK-
dc.contributor.authorZarowiecki, M-
dc.contributor.authorTsai, CT-
dc.contributor.authorLuo, H-
dc.contributor.authorStanojevic, B-
dc.contributor.authorLynn, C-
dc.contributor.authorLeung, AYH-
dc.contributor.authorZuna, J-
dc.contributor.authorZaliova, M-
dc.contributor.authorBornhauser, M-
dc.contributor.authorVON BONIN, M-
dc.contributor.authorLenhard, B-
dc.contributor.authorHuang, S-
dc.contributor.authorMufti, GJ-
dc.contributor.authorSo, CWE-
dc.date.accessioned2021-11-12T13:39:34Z-
dc.date.available2021-11-12T13:39:34Z-
dc.date.issued2021-
dc.identifier.citationScience Translational Medicine, 2021, v. 13 n. 582, p. article no. eabc4822-
dc.identifier.issn1946-6242-
dc.identifier.urihttp://hdl.handle.net/10722/307902-
dc.description.abstractChemoresistance 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.-
dc.languageeng-
dc.publisherAmerican Association for the Advancement of Science. The Journal's web site is located at http://www.sciencemag.org/marketing/stm/-
dc.relation.ispartofScience Translational Medicine-
dc.rightsScience Translational Medicine. Copyright © American Association for the Advancement of Science.-
dc.rightsThis is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in [Science Journal Title] on [Volume number and date], DOI: [insert DOI number].-
dc.titleFunctional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia-
dc.typeArticle-
dc.identifier.emailLeung, AYH: ayhleung@hku.hk-
dc.identifier.authorityLeung, AYH=rp00265-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1126/scitranslmed.abc4822-
dc.identifier.pmid33627486-
dc.identifier.scopuseid_2-s2.0-85101761336-
dc.identifier.hkuros330162-
dc.identifier.volume13-
dc.identifier.issue582-
dc.identifier.spagearticle no. eabc4822-
dc.identifier.epagearticle no. eabc4822-
dc.identifier.isiWOS:000622334400004-
dc.publisher.placeUnited States-

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