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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, 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 HSPC loss and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.

SUBMITTER: Pirillo C

PROVIDER: S-EPMC9131921 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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

Pirillo Chiara C Birch Flora F Tissot Floriane S FS Anton Sara Gonzalez SG Haltalli Myriam M Tini Valentina V Kong Isabella I Piot Cécile C Partridge Ben B Pospori Constandina C Keeshan Karen K Santamaria Salvatore S Hawkins Edwin E Falini Brunangelo B Marra Andrea A Duarte Delfim D Lee Chiu Fan CF Roberts Edward E Lo Celso Cristina C

Blood advances 20220501 10

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 ...[more]

PMID: 35157757

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

Publications

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

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