Extracellular Vesicles in Acute Leukemia: A Mesmerizing Journey With a Focus on Transferred microRNAs

Abstract

Despite their small size, the membrane-bound particles named extracellular vesicles (EVs) seem to play an enormous role in the pathogenesis of acute leukemia. From oncogenic hematopoietic stem cells (HSCs) to become leukemic cells to alter the architecture of bone marrow (BM) microenvironment, EVs are critical components of leukemia development. As a carrier of essential molecules, especially a group of small non-coding RNAs known as miRNA, recently, EVs have attracted tremendous attention as a prognostic factor. Given the importance of miRNAs in the early stages of leukemogenesis and also their critical parts in the development of drug-resistant phenotype, it seems that the importance of EVs in the development of leukemia is more than what is expected. To be familiar with the clinical value of leukemia-derived EVs, this review aimed to briefly shed light on the biology of EVs and to discuss the role of EV-derived miRNAs in the development of acute myeloid leukemia and acute lymphoblastic leukemia. By elaborating the advances and challenges concerning the isolation of EVs, we discuss whether EVs could have a prognostic value in the clinical setting for leukemia.

Keywords: acute lymphoblastic leukemia; acute myeloblastic leukemia; disease pathogenesis; extracellular vesicles; miRNAs; non-coding RNAs; prognosis factor.

FIGURE 1

AML cells are able to transfer miR-155 to another AML cell (Hornick et al., 2015). (A) MiR-155 and other elements are transferred to recipient cells via exosomes. (B) MiR-155 derived from exosomes is released into the recipient cell and inhibits the activated SH2 domain-containing inositol 5′-phosphatase1 (SHIP1) expression. Following the inhibition of SHIP1, the enhancement of AKT signaling promotes cell survival (Xue et al., 2014).

FIGURE 2

Apoptosis suppression by miR-125b might help APL cells survive in cytotoxic situation (Zhang et al., 2011). MiR-125b is a microRNA that targets Bak1. As miR-125 levels rise, Bak levels fall, and apoptosis decreases.

FIGURE 3

(A) Cancer-derived exosomes can transfer to MSCs and change MSCs. MSCs differentiated to cancer-associated fibroblast (CAF) in B.M microenvironment. (B) CAFs supports cancer cells via secreted content such as TGF-β, IL-11, IL-6, and chemokine. CAF secreted contents affect cancer cells and increase cancer cell proliferation, survival. (C) Cancer derived exosomes can also uptake by endothelial cells and induce angiogenesis. CAFs secreted content can also induce angiogenesis in endothelial cells (Padua and Massagué, 2009; Mineo et al., 2012; Pickup et al., 2013; Costanza et al., 2017).