MicroRNA-Containing Exosomes Promote AML Pathogenesis Via Stromal Remodeling and Suppression of Normal Hematopoiesis
Introduction. Acute myeloid leukemia (AML) is the most common acute leukemia in adults.1 It results from an abnormal accumulation of myeloblasts and is associated with a wide variety of genetic mutations.2 Symptoms include recurrent infection, anemia, and bleeding.3 The median age of diagnosis is 68 years and the five-year survival rate is 24%; this relatively high mortality is due to relapse, which occurs frequently, and the fact that traditional cytotoxic chemotherapy regimens are especially harmful to the older patient population that AML primarily affects.1 Leukemic blasts have been shown to display abnormal release of exosomes, small extracellular vesicles that play key roles in cell signaling in the bone marrow.4 Multiple studies have identified microRNA (miRNA) release in exosomes as driving the inhibition of normal hematopoiesis as well as observed stromal changes in the setting of AML. With regards to the bone marrow stroma, miRNAs have been shown to upregulate the DKK1 pathway, leading to reduced differentiation of osteoblasts and a decreased ability of the bone marrow to support hematopoietic stem cells (HSCs).5 Several miRNAs have been shown to directly inhibit hematopoiesis; an example is the targeting of the pro-hematopoietic transcription factor c-MYB by miR-155.3 Identification of miRNAs and the pathways they modulate may elucidate potential therapeutic strategies for AML that go beyond chemotherapy. Methods. In-vivo xenografts of AML cell lines and miRNA electroporation were used to analyze the effects of miRNAs on hematopoiesis and bone marrow function. A promising 2018 study used a mouse model to identify the specific anti-leukemic effects of miR-34c-5p. MiR-34c-5p was selected for study due to previously identified association with reduced patient mortality and better response to chemotherapy. Transduction of KG-1a AML cells with lentivirus constructs was used to overexpress miR-34c-5p in blasts. GW4869, an inhibitor of exosome release, was administered to increase the activity of miR-34c-5p in blasts.6 Results. Overexpression of miR-34c-5p was associated with increased senescence of AML cells. Blasts use RAB27B-mediated exosome shedding to traffic miR-34c-5p out of the cell and avoid senescence. RAB27B silencing increased intracellular miR-34c-5p levels and promoted blast senescence.6 Conclusions. Studies have described numerous interactions between miRNAs and molecular pathways involved in the hematopoietic arrest and stromal remodeling observed with AML. Overexpression of miR-34c-5p reduced mortality and increased senescence and apoptosis of blasts in vivo. This research provides promising evidence for the therapeutic potential of miRNAs in the treatment of AML.
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- Döhner H, Estey E, Grimwade D, et al. Diagnosis and Management of AML in Adults: 2017 ELN Recommendations from an International Expert Panel. Vol 129.; 2017. doi:10.1182/blood-2016-08-733196
- Hornick NI, Doron B, Abdelhamed S, et al. AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB. Sci Signal. 2016;9(444):1-10. doi:10.1126/scisignal.aaf2797
- Wallace JA, O’Connell RM. MicroRNAs and acute myeloid leukemia: Therapeutic implications and emerging concepts. Blood. 2017;130(11). doi:10.1182/blood-2016-10-697698
- Kumar B, Garcia M, Weng L, et al. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia. 2018;32(3):575-587. doi:10.1038/leu.2017.259
- Peng D, Wang H, Li L, et al. MiR-34c-5p promotes eradication of acute myeloid leukemia stem cells by inducing senescence through selective RAB27B targeting to inhibit exosome shedding. Leukemia. 2018;32(5):1180-1188. doi:10.1038/s41375-018-0015-2