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Theranostics 2019; 9(19):5642-5656. doi:10.7150/thno.34813 This issue Cite

Research Paper

Chronic myelogenous leukemia cells remodel the bone marrow niche via exosome-mediated transfer of miR-320

Xiaotong Gao^1*, Zhuo Wan^1*, Mengying Wei^2,3*, Yan Dong¹, Yingxin Zhao¹, Xutao Chen⁴, Zhelong Li⁵, Weiwei Qin^1✉, Guodong Yang^2,3✉, Li Liu^1✉

1. Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China.
2. State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
3. Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
4. Department of Implantation, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
5. Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, People's Republic of China.
^*These authors contributed equally to this work.

✉ Corresponding author: Li Liu (email: heamatoledu.cn). Correspondence may also be addressed to Guodong Yang (email: yanggdedu.cn) and Weiwei Qin (email: vivianq1126com)

Abstract

Rationale: Reciprocal interactions between leukemic cells and bone marrow mesenchymal stromal cells (BMMSC) remodel the normal niche into a malignant niche, leading to leukemia progression. Exosomes have emerged as an essential mediator of cell-cell communication. Whether leukemic exosomes involved in bone marrow niche remodeling remains unknown.

Methods: We investigated the role of leukemic exosomes in molecular and functional changes of BMMSC in vitro and in vivo. RNA sequencing and bioinformatics were employed to screen for miRNAs that are selectively sorted into leukemic exosomes and the corresponding RNA binding proteins.

Results: We demonstrated that leukemia cells significantly inhibited osteogenesis by BMMSC both in vivo and in vitro. Some tumor suppressive miRNAs, especially miR-320, were enriched in exosomes and thus secreted by leukemic cells, resulting in increased proliferation of the donor cells. In turn, the secreted exosomes were significantly endocytosed by adjacent BMMSC and thus inhibited osteogenesis at least partially via β-catenin inhibition. Mechanistically, miR-320 and some other miRNAs were sorted out into the exosomes by RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), as these miRNAs harbor the recognition site for HNRNPA1.

Conclusion: HNRNPA1-mediated exosomal transfer of miR-320 from leukemia cells to BMMSC is an important mediator of leukemia progression and is a potential therapeutic target for CML.

Keywords: chronic myelogenous leukemia, exosomes, bone marrow mesenchymal stromal cells, miR-320, HNRNPA1

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