RNA Trafficking by Acute Myelogenous Leukemia Exosomes

Abstract

Extrinsic signaling cues in the microenvironment of acute myelogenous leukemia (AML) contribute to disease progression and therapy resistance. Yet, it remains unknown how the bone marrow niche in which AML arises is subverted to support leukemic persistence at the expense of homeostatic function. Exosomes are cell membrane-derived vesicles carrying protein and RNA cargoes that have emerged as mediators of cell-cell communication. In this study, we examined the role of exosomes in developing the AML niche of the bone marrow microenvironment, investigating their biogenesis with a focus on RNA trafficking. We found that both primary AML and AML cell lines released exosome-sized vesicles that entered bystander cells. These exosomes were enriched for several coding and noncoding RNAs relevant to AML pathogenesis. Furthermore, their uptake by bone marrow stromal cells altered their secretion of growth factors. Proof-ofconcept studies provided additional evidence for the canonical functions of the transferred RNA. Taken together, our findings revealed that AML exosome trafficking alters the proliferative, angiogenic, and migratory responses of cocultured stromal and hematopoietic progenitor cell lines, helping explain how the microenvironmental niche becomes reprogrammed during invasion of the bone marrow by AML. Cancer Res; 73(2); 918-29. Ó2012 AACR.

Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts

“…[12][13][14] Exosome uptake induces phenotypic changes in target cells as exosome miRNAs can silence mRNA targets and influence cellular functions. 15 Exosomes released by acute myeloid leukemia cells affect the proliferation and migration of bone marrow (BM) stromal cells, 16,17 multiple myeloma exosomes enhance angiogenesis, 18 melanoma-derived exosomes reprogram the BM niche to support metastasis, 19 and miR-105 conveyed by breast cancer-derived exosomes destroys the endothelial barrier to promote metastasis. 20 In CLL, circulating exosomes may affect mesenchymal stem cells (MSCs) and endothelial cells (ECs), which are both present in the BM and lymphatic tissues, where they support leukemic cell survival 21,22 and are possible sources of cancerassociated fibroblast (CAF).…”

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

“…Exosomes and microvesicles are other cellular structures released from AML cells and serve to remodel the BM niche. Exosomes are membranous nano-sized (30-100 nm) vesicles derived from the endocytic compartment which is enriched with microRNAs (miRNA), small RNA and mRNA; whereas microvesicles are larger vesicles (> 1ml) produced by the shedding of the plasma membrane that is enriched with mRNA [37,38]. AML patients' plasma may contain CXCR4-expressing microparticles at concentrations higher than those of normal individuals, while the opposite may be true for CXCL12 concentrations [37].…”

“…These CD451 microparticles that may also contain truncated CXCR4 molecules strongly correlate with high white blood cell (WBC) counts and can transfer the CXCR4 molecule to AMLderived HL-60 cells increasing their BM homing in irradiated NOD/ SCID/b2null mice. In addition, distinct exosomes may contain miR150, miR210 and transcripts relevant to AML prognosis, treatment and niche function that may alter the behavior of bystander cells [38,39]. AML cells can also actively participate in the increase of BM microvascular density as they not only produce vascular endothelial growth factor (VEGF) and angiopoietins 1 and 2 (Ang-1 and -2), but they may also create autocrine and paracrine loops by expressing VEGF receptors or Tie2, the angiopoietin receptor [40][41][42].…”

Extracelluláris vesiculák és hematológiai malignitásokban játszott szerepük

“…Jóval kevesebb vizsgálat folyt hematológiai malignitások és az extracelluláris vesiculák kapcsolatára vonatkozóan [20,[26][27][28][29]. Ezeket mutatjuk be összefoglalónk hátralévő részében.…”

“…A blastokkal együtt tenyésztett niche jellegű sejtek felvették a vizsgált exosomákat, és kimutathatóan megváltoztatták azok növe-kedésifaktor-termelését. Ezek az eredmények arra utalnak, hogy a leukaemiás sejtek vesiculák révén befolyásolják, alakítják a csontvelői környezetüket [20,[33][34][35].…”