Targeting leukemia stem cells in vivo with antagomiR-126 nanoparticles in acute myeloid leukemia

Abstract

Current treatments for acute myeloid leukemia (AML) are designed to target rapidly dividing blast populations with limited success in eradicating the functionally distinct leukemia stem cell (LSC) population, which is postulated to be responsible for disease resistance and relapse. We have previously reported high miR-126 expression levels to be associated with a LSC-gene expression profile. Therefore, we hypothesized that miR-126 contributes to “stemness” and is a viable target for eliminating the LSC in AML. Here we first validate the clinical relevance of miR-126 expression in AML by showing that higher expression of this microRNA (miR) is associated with worse outcome in a large cohort of older (≥60 years) cytogenetically normal AML patients treated with conventional chemotherapy. We then show that miR-126 overexpression characterizes AML LSC-enriched cell subpopulations and contributes to LSC long-term maintenance and self-renewal. Finally, we demonstrate the feasibility of therapeutic targeting of miR-126 in LSCs with novel targeting nanoparticles (NP) containing antagomiR-126 resulting in in vivo reduction of LSCs likely by depletion of the quiescent cell subpopulation. Our findings suggest that by targeting a single miR, i.e., miR-126, it is possible to interfere with LSC activity, thereby opening potentially novel therapeutic approaches to treat AML patients.

Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia

“…In contrast to this result, we observed no effects on cell proliferation when miR-126 expression was modulated in AML bulk blasts. Instead, we found miR-126 to be essential for LSC homeostasis (2). Whether EGFL7 also has a role in LSCs, dependent on or independent from miR-126, has not yet been determined.…”

“…In patients with concomitant aberrant overexpression of miR-126, EGFL7 blockade could be combined with therapeutic interventions to down-regulate miR-126, to target the LSC compartment additionally. We have previously shown the feasibility of therapeutic manipulation of miR-126 with nanoparticle-conjugated oligonucleotides (NP-antagomiR-126) in a preclinical model (2). In this sense, combining EGFL7-inhibition with NP-antagomiR-126 therapies may improve the treatment of AML patients, because the blocking the growth-promoting functions of EGFL7 on bulk blasts would be combined with the targeting of the therapy-resistant LSCs by the NP-antagomiR-126.…”

“…miR-126 is located within intron 7 of a protein-coding gene known as Epithelial growth factor-like 7 (EGFL7) (3). Although we and others (2,4,5) have shown an important role for miR-126 in AML biology, we know of no studies that have been performed to understand the prognostic and functional implications of expression of its host gene, EGFL7, in AML.…”

“…Previously, our group demonstrated that increased miRNA-126-3p (miR-126) expression in patients with cytogenetically normal AML (CN-AML) correlated with shorter overall survival (OS). Furthermore, we found miR-126 to be essential for leukemia stem cell (LSC) homeostasis, and in vivo targeting of miR-126 in a patientderived xenograft model resulted in prolonged survival in secondary bone marrow transplant (BMT) recipients (2). miR-126 is located within intron 7 of a protein-coding gene known as Epithelial growth factor-like 7 (EGFL7) (3).…”

A Forecast of Targeting Leukemia Stem Cells by Nanomedicine

“…siRNA has been considered as one of the most promising candidate for gene therapy in cancer treatment, however their instability significantly limited their clinical applications [112]. Recently, Dorrance et al have successfully delivered antagomiR-126 into AML mouse models by using nanocarrier, in which LSCs were depleted [113].…”