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

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-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.

Studying Signaling Pathway Activation in TRAIL-Resistant Macrophage-Like Acute Myeloid Leukemia Cells

“…For example, chronic inflammation mediated by IL-1β is often associated with the emergence and progression of malignant tumors, as well as the direct regulation of myeloid cell differentiation and the signaling pathways that mediate the survival of leukemic cells [ 49 , 50 , 51 ]. Matrix metalloproteinases are involved in the migration of myeloid cells induced by an inflammation, and their suppression significantly reduces the viability and proliferation of AML cells [ 52 , 53 ].…”

MMP9-Associated Tumor Stem Cells, CCL1-Silenced Dendritic Cells, and Cytokine-Induced Killer Cells Have a Remarkable Therapeutic Efficacy for Acute Myeloid Leukemia by Activating T Cells

“…Matrix metalloproteinases (MMPs) have been verified to be involved in tumor metastasis by the degradation of the extracellular matrix (ECM) [ 49 ]. ECM modulation induced by MMPs has the dual effect of suppressing AML cells while improving the retention of healthy hematopoietic stem cells, tilting the competition between healthy and malignant hematopoiesis in favor of the former [ 50 ]. Inhibition of MMP expression may complement traditional AML treatment regimens and improve cytopenias associated with the loss of healthy hematopoietic stem and progenitor cells (HSPCs) [ 50 ].…”

Visualizing vasculature and its response to therapy in the tumor microenvironment

“…Importantly, inhibition of NO production improves treatment response to arabinosylcytosine in vivo 146 . A similar skull window model demonstrated that MMP inhibition reduced vascular permeability, suppressing AML infiltration and growth 147 .…”