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

Stefania Trino,Michele Santodirocco,Luciana De Luca,Angelo De Stradis,Alessandro Sgambato,Daniela Lamorte,Ilaria Laurenzana,Giovanni Calice,Antonella Caivano

doi:10.3389/fonc.2022.824562

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.

Highlights

Acute myeloid leukemia (AML) is a neoplastic disorder characterized by an uncontrolled increase of myeloid precursors and their accumulation in both peripheral blood (PB) and bone marrow (BM) [1]
As source of AML-extracellular vesicles (EVs) we used EVs isolated from supernatant of two AML cell lines, KG-1 and ME-1
We focused our attention on hematopoietic stem/progenitor cells (HSPCs) populations that include hematopoietic stem cells (HSC), multipotent progenitors (MPP), lymphoid-primed multipotent progenitors (LMPP), multilymphoid progenitors (MLP), common myeloid progenitors (CMP), granulocyte-macrophage progenitors (GMP), megakaryocyte-erythroid progenitors (MEP) and B and NK cell progenitors (B/NK)

Summary

Introduction

Acute myeloid leukemia (AML) is a neoplastic disorder characterized by an uncontrolled increase of myeloid precursors and their accumulation in both peripheral blood (PB) and bone marrow (BM) [1]. AML is the result of hematopoietic stem or progenitor cell transformation through the acquisition of different genetic mutations and chromosomal rearrangements that induce their differentiation block and an increased proliferation [2, 3]. Despite the current available therapeutic approaches, such as chemotherapy and allogeneic hematopoietic stem cell transplantation, AML patient outcome remains unsatisfactory with more than half of patients dying from disease [1]. Rapid clonal expansion of malignant cells in AML, occurring within the BM microenvironment, causes a replacement of heterogeneous hematopoietic and stromal cells, and impairs normal hematopoiesis and immune cells development [4]. The abnormally expanded malignant blasts, benefit from BM niche, and perturb it in order to induce a favorable microenvironment for leukemic progression [4–6]

Results

Discussion

Conclusion