Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia
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Zeisig, Bernd B.Fung, Tsz Kan
Zarowiecki, Magdalena
Tsai, Chiou Tsun
Luo, Huacheng
Stanojević, Boban
Lynn, Claire
Leung, Anskar Y.H.
Zuna, Jan
Zaliova, Marketa
Bornhauser, Martin
von Bonin, Malte
Lenhard, Boris
Huang, Suming
Mufti, Ghulam J.
So, Chi Wai Eric
Article (Published version)
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© 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science
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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. H...SC-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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Science Translational Medicine, 2021, 13, 582, eabc4822-Funding / projects:
- CRUK programme grant
- Blood Cancer UK research grant
- Kay Kendall Leukaemia Fund research grant
- Royal Society of London
- United States Department of Health & Human Services National Institutes of Health (NIH) - USA [R01CA 204044]
- Theme-based-Research Scheme, Research Grant Council, HKSAR [TR-702/20-N]
- 1946-6234
DOI: 10.1126/scitranslmed.abc4822
ISSN: 1946-6234 (Print); 1946-6242 (Online)
PubMed: 33627486
WoS: 000622334400004
Scopus: 2-s2.0-85101761336
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VinčaTY - JOUR AU - Zeisig, Bernd B. AU - Fung, Tsz Kan AU - Zarowiecki, Magdalena AU - Tsai, Chiou Tsun AU - Luo, Huacheng AU - Stanojević, Boban AU - Lynn, Claire AU - Leung, Anskar Y.H. AU - Zuna, Jan AU - Zaliova, Marketa AU - Bornhauser, Martin AU - von Bonin, Malte AU - Lenhard, Boris AU - Huang, Suming AU - Mufti, Ghulam J. AU - So, Chi Wai Eric PY - 2021 UR - https://vinar.vin.bg.ac.rs/handle/123456789/9142 AB - 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. T2 - Science Translational Medicine T1 - Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia VL - 13 IS - 582 SP - eabc4822 DO - 10.1126/scitranslmed.abc4822 ER -
@article{ author = "Zeisig, Bernd B. and Fung, Tsz Kan and Zarowiecki, Magdalena and Tsai, Chiou Tsun and Luo, Huacheng and Stanojević, Boban and Lynn, Claire and Leung, Anskar Y.H. and Zuna, Jan and Zaliova, Marketa and Bornhauser, Martin and von Bonin, Malte and Lenhard, Boris and Huang, Suming and Mufti, Ghulam J. and So, Chi Wai Eric", year = "2021", abstract = "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.", journal = "Science Translational Medicine", title = "Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia", volume = "13", number = "582", pages = "eabc4822", doi = "10.1126/scitranslmed.abc4822" }
Zeisig, B. B., Fung, T. K., Zarowiecki, M., Tsai, C. T., Luo, H., Stanojević, B., Lynn, C., Leung, A. Y.H., Zuna, J., Zaliova, M., Bornhauser, M., von Bonin, M., Lenhard, B., Huang, S., Mufti, G. J.,& So, C. W. E.. (2021). Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia. in Science Translational Medicine, 13(582), eabc4822. https://doi.org/10.1126/scitranslmed.abc4822
Zeisig BB, Fung TK, Zarowiecki M, Tsai CT, Luo H, Stanojević B, Lynn C, Leung AY, Zuna J, Zaliova M, Bornhauser M, von Bonin M, Lenhard B, Huang S, Mufti GJ, So CWE. Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia. in Science Translational Medicine. 2021;13(582):eabc4822. doi:10.1126/scitranslmed.abc4822 .
Zeisig, Bernd B., Fung, Tsz Kan, Zarowiecki, Magdalena, Tsai, Chiou Tsun, Luo, Huacheng, Stanojević, Boban, Lynn, Claire, Leung, Anskar Y.H., Zuna, Jan, Zaliova, Marketa, Bornhauser, Martin, von Bonin, Malte, Lenhard, Boris, Huang, Suming, Mufti, Ghulam J., So, Chi Wai Eric, "Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia" in Science Translational Medicine, 13, no. 582 (2021):eabc4822, https://doi.org/10.1126/scitranslmed.abc4822 . .