Acute Myeloid Leukemia Cells Functionally Compromise Hematopoietic Stem/Progenitor Cells Inhibiting Normal Hematopoiesis Through the Release of Extracellular Vesicles

Abstract

Acute myeloid leukemia (AML) is an aggressive and heterogeneous clonal disorder of hematopoietic stem/progenitor cells (HSPCs). It is not well known how leukemia cells alter hematopoiesis promoting tumor growth and leukemic niche formation. In this study, we investigated how AML deregulates the hematopoietic process of HSPCs through the release of extracellular vesicles (EVs). First, we found that AML cells released a heterogeneous population of EVs containing microRNAs involved in AML pathogenesis. Notably, AML-EVs were able to influence the fate of HSPCs modifying their transcriptome. In fact, gene expression profile of AML-EV-treated HSPCs identified 923 down- and 630 up-regulated genes involved in hematopoiesis/differentiation, inflammatory cytokine production and cell movement. Indeed, most of the down-regulated genes are targeted by AML-EV-derived miRNAs. Furthermore, we demonstrated that AML-EVs were able to affect HSPC phenotype, modifying several biological functions, such as inhibiting cell differentiation and clonogenicity, activating inflammatory cytokine production and compromising cell movement. Indeed, a redistribution of HSPC populations was observed in AML-EV treated cells with a significant increase in the frequency of common myeloid progenitors and a reduction in granulocyte-macrophage progenitors and megakaryocyte-erythroid progenitors. This effect was accompanied by a reduction in HSPC colony formation. AML-EV treatment of HSPCs increased the levels of CCL3, IL-1B and CSF2 cytokines, involved in the inflammatory process and in cell movement, and decreased CXCR4 expression associated with a reduction of SDF-1 mediated-migration. In conclusion, this study demonstrates the existence of a powerful communication between AML cells and HSPCs, mediated by EVs, which suppresses normal hematopoiesis and potentially contributes to create a leukemic niche favorable to neoplastic development.

Transcriptomics of mussel transmissible cancer MtrBTN2 suggests accumulation of multiple cancerous traits and oncogenic pathways shared among bilaterians

“…During MtrBTN2 disease progression, we also observe a drastic decrease in the number of host hemocytes, progressively replaced by circulating MtrBTN2 cells, which can represent over 95% of the circulating cells in cancerous mussels (18, 21). To date, it remains to be determined whether MtrBTN2 cells outcompete regular hemocytes in the hemolymph or whether they interfere with hematopoiesis, as seen for some human leukemias (93). Still, the combination of fewer circulating hemocytes and the immune incompetence of MtrBTN2 cells could have dramatic consequences for the host health and could lead to lethal opportunistic systemic infections (94).…”

Transcriptomics of mussel transmissible cancer MtrBTN2 suggests accumulation of multiple cancer traits and oncogenic pathways shared among bilaterians

“…During MtrBTN2 disease progression, we also observe a drastic decrease in the number of host haemocytes, which are progressively replaced by circulating MtrBTN2 cells, which can represent over 95% of the circulating cells in cancerous mussels [ 19 , 22 ]. It remains to be determined whether MtrBTN2 cells outcompete normal haemocytes in the haemolymph or whether they interfere with haematopoiesis, as seen in some human leukaemias [ 98 ]. Still, the combination of fewer circulating haemocytes and the immune incompetence of MtrBTN2 cells could have dramatic consequences for the host health, leading to lethal opportunistic systemic infections [ 99 ].…”

“…During MtrBTN2 disease progression, we also observe a drastic decrease in the number of host haemocytes, which are progressively replaced by circulating MtrBTN2 cells, which can represent over 95% of the circulating cells in cancerous mussels [19,22]. It remains to be determined whether MtrBTN2 cells outcompete normal haemocytes in the haemolymph or whether they interfere with haematopoiesis, as seen in some human leukaemias [98].…”

Extracellular vesicles in hematological malignancies: EV-dence for reshaping the tumoral microenvironment

“…Dendritic cells (DCs) treated with AML patient-derived EVs in comparison to K562 (chronic myelogenous leukemia cell line)-derived EVs were shown to have a notable decrease in specific cytotoxicity, further contributing to the immunosuppressive environment fostered by the malignancy ( 44 ). In addition to immune response modulation, AML-derived sEVs can shape the bone marrow niche into a leukemia-permissive ME, hampering normal hematopoiesis ( 45 , 46 ). AML-derived sEVs were shown to have increased dipeptidyl-peptidase 4 (DPP4) activity compared to healthy donors.…”