advancesadv2021004321.pdf (3.79 MB)
Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness.
journal contributionposted on 2022-05-26, 11:06 authored by Chiara Pirillo, Flora Birch, Floriane Tissot, Sara Gonzalez Anton, Myriam Haltalli, Valentina Tini, Isabella Kong, Cécile Piot, Ben Partridge, Costandina Pospori, Karen Keeshan, Salvatore Santamaria, Edwin Hawkins, Brunangelo Falini, Andrea Marra, Delfim Duarte, Chiu Fan Lee, Edward Roberts, Cristina Lo Celso
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-treated mice 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 inhibition could 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.