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Acute myeloid leukaemia niche regulates response to L‐asparaginase

Michelozzi, I; Granata, V; De Ponti, G; Alberti, G; Tomasoni, C; Antolini, L; Gambacorti-Passerini, C; ... Serafini, M; + view all (2019) Acute myeloid leukaemia niche regulates response to L‐asparaginase. British Journal of Haematology , 186 (3) pp. 420-430. 10.1111/bjh.15920. Green open access

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Abstract

Eradicating the malignant stem cell is the ultimate challenge in the treatment of leukaemia. Leukaemic stem cells (LSC) hijack the normal haemopoietic niche, where they are mainly protected from cytotoxic drugs. The anti‐leukaemic effect of L‐asparaginase (ASNase) has been extensively investigated in acute lymphoblastic leukaemia, but only partially in acute myeloid leukaemia (AML). We explored the susceptibility of AML‐LSC to ASNase as well as the role of the two major cell types that constitute the bone marrow (BM) microenvironment, i.e., mesenchymal stromal cells (MSC) and monocytes/macrophages. Whilst ASNase was effective on both CD34+CD38+ and CD34+CD38− LSC fractions, MSC and monocytes/macrophages partially counteracted the effect of the drug. Indeed, the production of cathepsin B, a lysosomal cysteine protease, by BM monocytic cells and by AML cells classified as French‐American‐British M5 is related to the inactivation of ASNase. Our work demonstrates that, while MSC and monocytes/macrophages may provide a protective niche for AML cells, ASNase has a cytotoxic effect on AML blasts and, importantly, LSC subpopulations. Thus, these features should be considered in the design of future clinical studies aimed at testing ASNase efficacy in AML patients.

Type: Article
Title: Acute myeloid leukaemia niche regulates response to L‐asparaginase
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/bjh.15920
Publisher version: https://doi.org/10.1111/bjh.15920
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Acute myeloid leukaemia, asparaginase, leukaemic stem cells, bone marrow microenvironment, cathepsin B
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10073555
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