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

doi:10.1007/s12015-017-9762-0

. 2017 Dec;13(6):817-825.

doi: 10.1007/s12015-017-9762-0.

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

Juliana Barrera-Ramirez¹, Jessie R Lavoie², Harinad B Maganti^{1

3

4}, William L Stanford^{1

3

4

5}, Caryn Ito^{1

5}, Mitchell Sabloff⁶, Marjorie Brand^{1

5}, Michael Rosu-Myles^{2

4}, Yevgeniya Le^{1

7}, David S Allan^{8

9

10

11

12}

Affiliations

¹ Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
² Centre for Biologics Evaluation, Biologics Genetic and Therapies Directorate, Health Products Food Branch, Health Canada, Ottawa, ON, Canada.
³ Ottawa Institute of Systems Biology, Ottawa, ON, Canada.
⁴ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
⁵ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
⁶ Hematology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada.
⁷ Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, ON, Canada.
⁸ Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. daallan@ohri.ca.
⁹ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada. daallan@ohri.ca.
¹⁰ Hematology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada. daallan@ohri.ca.
¹¹ Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, ON, Canada. daallan@ohri.ca.
¹² Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada. daallan@ohri.ca.

PMID: 28918518
PMCID: PMC5730624
DOI: 10.1007/s12015-017-9762-0

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

Juliana Barrera-Ramirez et al. Stem Cell Rev Rep. 2017 Dec.

. 2017 Dec;13(6):817-825.

doi: 10.1007/s12015-017-9762-0.

Authors

Affiliations

¹ Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
² Centre for Biologics Evaluation, Biologics Genetic and Therapies Directorate, Health Products Food Branch, Health Canada, Ottawa, ON, Canada.
³ Ottawa Institute of Systems Biology, Ottawa, ON, Canada.
⁴ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
⁵ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
⁶ Hematology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada.
⁷ Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, ON, Canada.
⁸ Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. daallan@ohri.ca.
⁹ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada. daallan@ohri.ca.
¹⁰ Hematology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada. daallan@ohri.ca.
¹¹ Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, ON, Canada. daallan@ohri.ca.
¹² Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada. daallan@ohri.ca.

PMID: 28918518
PMCID: PMC5730624
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.

Keywords: Acute myeloid leukemia; Bone marrow; Exosome; Mesenchymal stromal cells; MicroRNA.

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Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

**Fig. 1**
Volcano Plot of microRNA isolated from exosomes of AML-derived MSCs and control MSCs. The log₂ of microRNA levels in AML-derived samples in comparison to healthy control samples (fold-change) is plotted against the –log₁₀ of the p value in a Student’s t test after comparing the mean fold change. A total of 3 microRNA species were significantly reduced (more than 1.5-fold reduced or –log₂(0.6) and p < 0.05 or –log₁₀(1.3)) in AML-derived samples compared with controls and 2 microRNA species were significantly increased. The specific microRNA species are presented in Table 2

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References

1. Ayala F, Dewar R, Kieran M, Kalluri R. Contribution of bone marrow microenvironment to leukemogenesis and leukemia progression. Leukemia. 2009;23:2233–2241. doi: 10.1038/leu.2009.175. - DOI - PMC - PubMed
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1. Roodhart JML, Daenen LGM, Stigter, et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell. 2011;20:370–383. doi: 10.1016/j.ccr.2011.08.010. - DOI - PubMed
1. Ishikawa F, Yoshida Y, Saito Y, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone marrow endosteal region. Nature Biotechnology. 2007;25:1315–1321. doi: 10.1038/nbt1350. - DOI - PubMed
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[1] Ayala F, Dewar R, Kieran M, Kalluri R. Contribution of bone marrow microenvironment to leukemogenesis and leukemia progression. Leukemia. 2009;23:2233–2241. doi: 10.1038/leu.2009.175. - DOI - PMC - PubMed

[2] Ayala F, Dewar R, Kieran M, Kalluri R. Contribution of bone marrow microenvironment to leukemogenesis and leukemia progression. Leukemia. 2009;23:2233–2241. doi: 10.1038/leu.2009.175. - DOI - PMC - PubMed

[3] Meads MB, Gatenby RA, Dalton WS. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nature Reviews. Cancer. 2009;9:665–674. doi: 10.1038/nrc2714. - DOI - PubMed

[4] Meads MB, Gatenby RA, Dalton WS. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nature Reviews. Cancer. 2009;9:665–674. doi: 10.1038/nrc2714. - DOI - PubMed

[5] Roodhart JML, Daenen LGM, Stigter, et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell. 2011;20:370–383. doi: 10.1016/j.ccr.2011.08.010. - DOI - PubMed

[6] Roodhart JML, Daenen LGM, Stigter, et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell. 2011;20:370–383. doi: 10.1016/j.ccr.2011.08.010. - DOI - PubMed

[7] Ishikawa F, Yoshida Y, Saito Y, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone marrow endosteal region. Nature Biotechnology. 2007;25:1315–1321. doi: 10.1038/nbt1350. - DOI - PubMed

[8] Ishikawa F, Yoshida Y, Saito Y, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone marrow endosteal region. Nature Biotechnology. 2007;25:1315–1321. doi: 10.1038/nbt1350. - DOI - PubMed

[9] Hertenstein B, Hambach L, Bacigalupo A, Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation et al. Development of leukemia in donor cells after allogeneic stem cell transplantation—a survey of the European Group for Blood and Marrow Transplantation. Haematolgica. 2005;90:969–975. - PubMed

[10] Hertenstein B, Hambach L, Bacigalupo A, Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation et al. Development of leukemia in donor cells after allogeneic stem cell transplantation—a survey of the European Group for Blood and Marrow Transplantation. Haematolgica. 2005;90:969–975. - PubMed

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

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

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