The metalloproteinase inhibitor Prinomastat 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 mechanism behind HSPC decline is 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. Numerous human leukemia types, particularly MLL-AF9 samples, show high expression levels of multiple matrix metalloproteinases (MMPs). Therefore, we evaluate the therapeutic potential of the MMP inhibitor (MMPI) prinomastat. IVM analyses of treated mice reveal reduced vascular permeability and healthy cell clusters in circulation, and lower AML cell speed. Furthermore, treated mice have decreased BM infiltration, increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Overall, our results suggest that MMPIs 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.