TY  - 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 . .