Acute lymphoblastic leukemia-secreted miRNAs induce a proinflammatory microenvironment and promote the activation of hematopoietic progenitors

Abstract

Leukemogenesis is proposed to result from the continuous interplay between inducive bone marrow (BM) microenvironments and malignant precursor cells. Recent findings point toward an abnormal production of proinflammatory mediators within the BM from acute lymphoblastic leukemia (ALL) patients, although the mechanism underlying this phenomenon is uncertain. Here, we have identified 3 miRNAs, miR-146a-5p, miR-181b-5p, and miR-199b-3p, as potential candidates for TLR8 ligation, which are overexpressed in ALL and show agonist functional binding. When purified from ALL exosomes, they demonstrated their capacity of inducing cytokine production by both, hematopoietic and stromal BM cells. Of note, the exposure of BM cells from ALL patients to the proinflammatory milieu resulting from these miRNAs agonist activity revealed the proliferation of normal progenitors, while poor effects were recorded in the leukemic counterpart. The unconventional roles of the tumor-secreted miRNAs as TLR8 agonist ligands may provide a novel mechanism contributing a

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

“…Furthermore, miR-34a-5p overexpression coincides with reductions in WNT and β-catenin expression and, consequently, osteogenic differentiation ( 99 ). Hematopoietic stem cell populations are gravely affected by ALL shed EVs, altered cytokine secretion, exhaustion, and failure to maintain HSC niche can be caused by these vesicles ( 94 , 97 , 100 ). Overexpressed miRs in ALL such as miR-146a-5p, miR-181b-5p and miR-199b-3p were shown to functionally bind to TLR8 in hematopoietic cells and BM-MSCs, promoting NF-kB activation and the subsequent secretion of proinflammatory cytokines aiding in the expansion of early hematopoietic cell populations ( 94 ).…”

“…Hematopoietic stem cell populations are gravely affected by ALL shed EVs, altered cytokine secretion, exhaustion, and failure to maintain HSC niche can be caused by these vesicles ( 94 , 97 , 100 ). Overexpressed miRs in ALL such as miR-146a-5p, miR-181b-5p and miR-199b-3p were shown to functionally bind to TLR8 in hematopoietic cells and BM-MSCs, promoting NF-kB activation and the subsequent secretion of proinflammatory cytokines aiding in the expansion of early hematopoietic cell populations ( 94 ). Eventually, this interaction leads to the establishment of a tumor microenvironment-hematopoietic feedback loop facilitating disease progression ( 94 ).…”

“…Overexpressed miRs in ALL such as miR-146a-5p, miR-181b-5p and miR-199b-3p were shown to functionally bind to TLR8 in hematopoietic cells and BM-MSCs, promoting NF-kB activation and the subsequent secretion of proinflammatory cytokines aiding in the expansion of early hematopoietic cell populations ( 94 ). Eventually, this interaction leads to the establishment of a tumor microenvironment-hematopoietic feedback loop facilitating disease progression ( 94 ). Furthermore, Heat shock protein 70 (HSP70) + ALL blast EVs rich in cholesterol target murine HSPCs in an ex vivo model and disrupt their quiescence by altering their mitochondrial energy metabolism and leading to an eventual exhaustion of these cells thereby affecting hematopoiesis ( 97 ).…”

“…Interactions between Acute lymphoid leukemia (ALL) blasts and the bone marrow ME are crucial to maintain malignant cell self-renewal, expansion, and chemoresistance necessary for leukemic development (78,(94)(95)(96)(97)(98). Pleckstrin homology domain family M member 1 (PLEKHM1) deficiency in the bone marrow microenvironment accelerated BCR-ABL + B-ALL disease progression by altering MSC EV cargo (98).…”

Tumour‑derived exosomes and their emerging roles in leukaemia (Review)

“…Exosomes secreted by tumour cells contain miRNAs, such as miR-146a-5p, miR-181b-5p and miR-199b-3p, that bind to Toll-like receptor (TLR)8 on the surface of bone marrow mesenchymal stromal cells (BM-MSCs). This activates inflammatory pathways and remodels the tumour microenvironment (TME) through TLR8 signalling, significantly reducing the haematopoietic capacity of normal HSCs and promoting the progression of ALL ( 28 , 29 ).…”