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Acute myeloid leukaemia niche regulates response to L‐asparaginase
Author(s) -
Michelozzi Ilaria M.,
Granata Valentina,
De Ponti Giada,
Alberti Gaia,
Tomasoni Chiara,
Antolini Laura,
GambacortiPasserini Carlo,
Gentner Bernhard,
Dazzi Francesco,
Biondi Andrea,
Coliva Tiziana,
Rizzari Carmelo,
Pievani Alice,
Serafini Marta
Publication year - 2019
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.15920
Subject(s) - haematopoiesis , cd38 , bone marrow , cytotoxic t cell , cancer research , cd34 , stem cell , immunology , myeloid , mesenchymal stem cell , medicine , biology , microbiology and biotechnology , in vitro , pathology , biochemistry
Summary 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.