Metalloproteinase inhibition reduces AML growth, prevents stem cell loss and improves chemotherapy effectiveness

Pirillo, C. et al. (2022) Metalloproteinase inhibition reduces AML growth, prevents stem cell loss and improves chemotherapy effectiveness. Blood Advances, 6(10), pp. 3126-3141. (doi: 10.1182/bloodadvances.2021004321) (PMID:35157757)

Abstract

Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. Its prognosis remains poor, highlighting the need for new therapeutic and precision medicine approaches. AML symptoms often include cytopenias, linked to loss of healthy hematopoietic stem and progenitor cells (HSPCs). The mechanisms behind HSPC decline are complex and still poorly understood. Here, intravital microscopy (IVM) of a well-established experimental model of AML allows direct observation of the interactions between healthy and malignant cells in the bone marrow (BM), suggesting that physical dislodgment of healthy cells by AML through damaged vasculature may play an important role. Multiple matrix metalloproteinases (MMPs), known to remodel extracellular matrix remodeling, are expressed by AML cells and the BM microenvironment. We reason MMPs could be involved in cell displacement and vascular leakiness, therefore we evaluate the therapeutic potential of MMP pharmacological inhibition using the broad-spectrum inhibitor prinomastat. IVM analyses of prinomastat-treatedmice reveal reduced vascular permeability and healthy cell clusters in circulation, and lower AML infiltration, proliferation and cell migration. Furthermore, treated mice have increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Analysis of a human AML transcriptomic database reveals widespread MMP deregulation, and human AML cells show susceptibility to MMP inhibition. Overall, our results suggest that MMP inhibitioncould be a promising complementary therapy to reduce AML growth and limit the loss of HSPC and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.

• Item Type: Articles
• Additional Information: This work was supported by Blood Cancer UK (Gordon Piller PhD studentship to C.P.), Cancer Research UK (Programme Foundation award C36195/A26770 to C.L.C. and PhD studentship C36195/A27830 to S.G.A.), the Wellcome trust (PhD studentship 105398/Z/14/Z to M.H., Investigator award 212304/Z/18/Z to C.L.C.), BBSRC (PhD studentship BB/M011178/1 to B.P.), Associazione Italiana per la Ricerca sul Cancro (AIRC) to B.F..
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Keeshan, Dr Karen and Roberts, Dr Ed
• Authors: Pirillo, C., Birch, F., Tissot, F., Anton, S. G., Haltalli, M., Tini, V., Kong, I., Piot, C., Partridge, B., Pospori, C., Keeshan, K., Santamaria, S., Hawkins, E., Falini, B., Marra, A., Duarte, D., Lee, C. F., Roberts, E., and Celso, C. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Blood Advances
• Publisher: American Society of Hematology
• ISSN: 2473-9529
• ISSN (Online): 2473-9537
• Published Online: 14 February 2022
• Copyright Holders: Copyright © 2022 American Society of Hematology
• First Published: First published in Blood Advances 6(10): 3126-2141
• Publisher Policy: Reproduced under a Creative Commons License