Platelet Microparticles Protect Acute Myelogenous Leukemia Cells against Daunorubicin-Induced Apoptosis.

Daniel Cacic,Oddmund Nordgård,Håkon Reikvam,Peter Meyer,Tor Hervig

doi:10.3390/cancers13081870

Abstract

Simple SummaryActivated or apoptotic platelets both shed platelet microparticles that are proven to be internalized by many different cell types, including cancer cells. Here, we have investigated whether platelet microparticles can transfer their contents to the monocytic leukemia cell line THP-1 and if this could change cell activity and resistance to chemotherapy. We show that platelet microparticles were internalized by THP-1 cells and that platelet-associated microRNAs were elevated after a brief co-incubation. Furthermore, differentiation toward macrophages was induced and cell cycle progression, proliferation, and mitochondrial activity were decreased. Co-incubation with platelet microparticles increased chemotherapy resistance, which also was evident in acute myelogenous leukemia cells from patient samples, and it could be explained by the decrease in cell activity. Thus, platelet microparticles may have a role in the evolution of acute myelogenous leukemia and contribute to development of chemotherapy resistance, making them an interesting target for treatment.The role of platelets in cancer development and progression is increasingly evident, and several platelet–cancer interactions have been discovered, including the uptake of platelet microparticles (PMPs) by cancer cells. PMPs inherit a myriad of proteins and small RNAs from the parental platelets, which in turn can be transferred to cancer cells following internalization. However, the exact effect this may have in acute myelogenous leukemia (AML) is unknown. In this study, we sought to investigate whether PMPs could transfer their contents to the THP-1 cell line and if this could change the biological behavior of the recipient cells. Using acridine orange stained PMPs, we demonstrated that PMPs were internalized by THP-1 cells, which resulted in increased levels of miR-125a, miR-125b, and miR-199. In addition, co-incubation with PMPs protected THP-1 and primary AML cells against daunorubicin-induced cell death. We also showed that PMPs impaired cell growth, partially inhibited cell cycle progression, decreased mitochondrial membrane potential, and induced differentiation toward macrophages in THP-1 cells. Our results suggest that this altering of cell phenotype, in combination with decrease in cell activity may offer resistance to daunorubicin-induced apoptosis, as serum starvation also yielded a lower frequency of dead and apoptotic cells when treated with daunorubicin.

Highlights

Acute myelogenous leukemia (AML) is a bone marrow malignancy originating in hematopoietic stem and progenitor cells [1,2,3]
To examine whether platelet microparticles could be internalized by acute myelogenous leukemia (AML) cells, we cultured cells from the monocytic AML cell line THP-1, with acridine orange (AO)-stained
There was a platelet microparticles (PMPs) concentration-dependent increase of fluorescence in the co-incubated cells, and fluorescence microscopy revealed that that the stain was dispersed within the cell nucleus and not located to bound microparticles (Figure 1A,B)

Summary

Introduction

Acute myelogenous leukemia (AML) is a bone marrow malignancy originating in hematopoietic stem and progenitor cells [1,2,3]. The average 5-year survival rate for de novo disease is approximately 50% in younger patients [4], but this may vary widely depending on the occurrence of a selection of genetic aberrances. LeukemiaNet genetic risk stratification of AML, survival varies from 20% to over 60% [5]. Curative treatment involves intensive chemotherapy and, for select high-risk patient groups, the addition of consolidating treatment with allogenic stem cell transplantation, which carries the risk of a fatal outcome [6]. Platelet–cancer interactions are becoming increasingly evident, and there is proof of cancer disease fundamentally altering the platelet transcriptome [7]. Platelets are important mediators for the development and maintenance of the cancer cell microenvironment [12,13]

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