Micro-RNA Profiling of Exosomes from Marrow-Derived Mesenchymal Stromal Cells in Patients with Acute Myeloid Leukemia: Implications in Leukemogenesis

Mitchell Sabloff,Marjorie Brand,William L. Stanford,Yevgeniya Le,Harinad B. Maganti,Michael Rosu-Myles,Juliana Barrera-Ramirez,Jessie R. Lavoie,Caryn Ito,David S. Allan

doi:10.1007/s12015-017-9762-0

Abstract

Gene regulatory networks in AML may be influenced by microRNAs (miRs) contained in exosomes derived from bone marrow mesenchymal stromal cells (MSCs). We sequenced miRs from exosomes isolated from marrow-derived MSCs from patients with AML (n = 3) and from healthy controls (n = 3; not age-matched). Known targets of mIRs that were significantly different in AML-derived MSC exosomes compared to controls were identified. Of the five candidate miRs identified by differential packaging in exosomes, only miR-26a-5p and miR-101-3p were significantly increased in AML-derived samples while miR-23b-5p, miR-339-3p and miR-425-5p were significantly decreased. Validation of the predicted change in gene expression of the potential targets was investigated by interrogating gene expression levels from public datasets of marrow-derived CD34-selected cells from patients with AML (n = 69) and healthy donors (n = 40). Two molecules with decreased gene expression in AML (EZH2 and GSK3β) were predicted by the miR profiling and have been previously implicated in AML while three molecules were increased in AML-derived cells and have not been previously associated with leukemogenesis (KRBA2, RRBP1 and HIST2H 2BE). In summary, profiling miRs in exosomes from AML-derived MSCs allowed us to identify candidate miRs with potential relevance in AML that could yield new insights regarding leukemogenesis or new treatment strategies.

Highlights

Perturbations in the bone marrow microenvironment in acute myeloid leukemia (AML) favor the selective progression of leukemia over normal hematopoiesis [1]
By comparing gene expression levels of potential targets of specific miRs in leukemic cells compared with normal hematopoietic progenitors, we have identified novel regulatory pathways implicated in mesenchymal stromal cells (MSCs)-derived exosomal miR signalling in AML
Gene regulatory networks in AML may be influenced by microRNAs contained in MSC-derived exosomes

Summary

Introduction

Perturbations in the bone marrow microenvironment in acute myeloid leukemia (AML) favor the selective progression of leukemia over normal hematopoiesis [1]. Leukemia cells may contain intrinsic mechanisms for chemo-resistance and disease progression, changes in gene regulatory. Stem Cell Rev and Rep (2017) 13:817–825 networks induced by extrinsic signals from the tumour microenvironment have been demonstrated in recent preclinical animal models [2, 3]. The occurrence of donor derived leukemia following bone marrow transplantation supports the concept of a damaged microenvironment that is permissive to leukemia development [5]. Signals arising within the microenvironment may be central to leukemic progression by altering gene regulatory networks within leukemic cells that enhance their competitive advantage at the expense of normal progenitors. Identifying specific signalling pathways that may be implicated and defining the origin of signals within the marrow microenvironment have proven challenging

Methods

Results

Conclusion