‘One way, or another, I’m gonna find ya’: miR-221-3p finds its targets via small extracellular vesicles

In this issue of Haematologica, Li et al. report yet another mechanism by which the ubiquitously oncogenic miR-221-3p locates its targets, through small extracellular vesicle (sEV)-mediated autocrine and paracrine actions to promote leukemogenesis.¹ Extracellular vesicles (EV) are lipid-bilayer enclosed structures released by cells into the extracellular (EC) space. EV are classified into three different subclasses based on size: sEV, previously known as exosomes, are the smallest, ranging from 30-150 nm in diameter; apoptotic bodies that are 50-5,000 nm in diameter; and microvesicles that range from 100-1,000 nm in diameter.² EV payloads consist of various cellular components including proteins, lipids and DNA, RNA and microRNA (miRNA) that can participate in intercellular signal transduction.

Recent studies have revealed that the unique payload composition of sEV can contribute to the progression of acute myeloid leukemia (AML) by promoting intercellular signaling among cells within the bone marrow (BM) niche. In particular, miRNA transferred from AML cells to non-malignant cells of the BM niche have been demonstrated to promote leukemogenesis through paracrine suppression of normal hematopoiesis by inhibiting hematopoietic stem and progenitor cells (HSPC), a consequence which contributes to a favorable leukemogenic BM niche.² Examples include exosomal mir-150 and mir-155, both found to suppress HSPC primarily through inhibition of c-myb.³ Similarly, mir-548ac was found to be transported in AML-sEV and could suppress normal hematopoiesis by targeting TRIM28 leading to subsequent STAT3 activation.⁴

Additionally, sEV-miRNA can function in an autocrine manner by promoting oncogenic properties of neighboring AML cells.² To complicate matters, sEV can also be derived from bone marrow stromal cells (BMSC). For instance, in acute lymphoblastic leukemia (ALL), mir-181a was found to be enriched in exosomes derived from both pediatric patient samples and cell lines.⁵ Exposure of exosomes containing elevated mir-181a promoted cell proliferation by upregulating PCNA and Ki67, and cell survival by upregulating prosurvival genes (MCL1 and BCL2) and downregulating pro-apoptotic genes (BAX and BAD).⁵ Another study found that BMSC from AML patients produced sEV with higher expression of miR-26-5p compared to healthy controls.⁶ Exposure of these sEV to AML cells promoted their proliferation through inhibition of GSKβ and activation of Wnt/β-catenin signaling.⁶

In this study, Li et al. performed high-throughput profiling of miRNA in sEV to identify the miRNA that play key roles in intercellular signaling in the BM niche.¹ They identified that miR-221-3p was among the most highly enriched AML-sEV and was found to promote AML cell growth while simultaneously impairing HSPC cell growth.¹ miR-221 is an established tumor promoting oncomiR,⁷ and it has also been demonstrated that miR-221-3p is transported in sEV derived from BMSC.⁸ Li et al. now demonstrate that miR-221-3p is transported in AML-derived sEV and contributes to both autocrine and paracrine signaling. The delivery of miR-221-3p to AML cells via sEV was observed to induce cell cycle progression while concurrently suppressing apoptosis by inhibiting Gbp2 and regulating PI3K/Akt signaling downstream.¹ Additionally, sEV miR-221-3p exhibited a selective paracrine effect on HSPC, impeding the erythroid differentiation of normal HSPC and consequently reducing their colony-forming capacity in both in vitro and ex vivo settings.¹ While many miRNA identified in sEV seem to affect either AML cells or HSPC exclusively, this study’s findings highlight an sEV miRNA capable of impacting both cell types, thereby orchestrating a “two-pronged impact” on the BM niche to promote leukemogenesis. Despite this, the exact molecular mechanism of sEV miR-221-3p-mediated suppression of normal hematopoiesis remains unknown. Does the sEV miR-221-3p/Gbp2/PI3K/Akt mechanism also facilitate HSPC suppression, or is there a cell-type dependent mechanism that leads to this “two-pronged impact”? Nonetheless, given these observations, targeting miR-221-3p shows promise as a therapeutic strategy, as its inhibition could not only disrupt its intracellular signaling but also mitigate its intercellular effects within the BM niche.

Figure 1.Small extracellular vesicles miR-221-3p promotes leukemogenesis through autocrine and paracrine signaling in the bone marrow niche. Acute myelod leukemia (AML)-derived small extracellular vesicles (sEV) containing miR-221-3p can support AML cell growth in an autocrine manner by promoting cell cycle progression and inhibiting apoptosis, in part through inhibiting Gbp2 and regulation of PI3K/Akt signaling. Simultaneously, sEV miR-221-3p can suppress normal hematopoiesis by suppressing hemtopoietic stem and progenitor cell (HSPC) differentiation in a paracrine manner. These concurrent autocrine and paracrine functions of sEV miR-221-3p consist of a “two-pronged impact” on the bone marrow niche that ultimately favors leukemogenesis.

sEV miR-221-3p holds potential as a clinical biomarker to enhance patient stratification in AML. While the concept of using sEV as biomarkers is not novel, further refinement of most effective miRNA is necessary before its practical application. Specifically, miRNA present in circulating sEV could serve as minimally invasive indicators of disease prognosis and progression.⁹ For instance, elevated serum sEV-mir-10b levels have been identified as an independent predictor of poor prognosis in AML patients, correlating with shorter survival times.¹⁰ Cellular miR-221-3p has previously been suggested as a valuable biomarker across various cancers,⁷ indicating the significant clinical potential of its sEV counterpart. This study identifies its potential to serve as a novel specific paracrine biomarker. Future studies should focus on determining whether sEV containing miR-221-3p circulate in the periphery and whether sEV miR-221-3p levels hold prognostic and predictive value. In sum, Li et al. provide evidence that the oncogenic function of miR-221-3p can be transmitted in a paracrine manner, thus targeting miR-221-3p harbored in sEV presents a promising target that can be leveraged theranostically.

Footnotes

• Received March 28, 2024
• Accepted April 11, 2024

Correspondence

L. Salmena leonardo.salmena@utoronto.ca

Disclosures

No conflicts of interest to disclose.