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.
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Michelozzi Manuscript tot BJH-2018-02094 R1.pdf - Accepted Version Download (9MB) | Preview |
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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