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Br J Haematol. 2019 May 1. doi: 10.1111/bjh.15920. [Epub ahead of print]

Acute myeloid leukaemia niche regulates response to L-asparaginase.

Author information

1
M. Tettamanti Research Centre, Department of Paediatrics, University of Milano-Bicocca, Monza, Italy.
2
Centro di Biostatistica per L'epidemiologia Clinica, Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
3
Department of Haematology, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy.
4
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.
5
Department of Haemato-Oncology, Rayne Institute, King's College London, London, UK.
6
Department of Paediatrics, Paediatric Haematology-Oncology Unit, Fondazione MBBM/San Gerardo Hospital, Monza, Italy.

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.

KEYWORDS:

acute myeloid leukaemia; asparaginase; bone marrow microenvironment; cathepsin B; leukaemic stem cells

PMID:
31044436
DOI:
10.1111/bjh.15920

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