Abstract
Abstract Twist-1, a basic helix-loop-helix transcription factor, regulates embryogenesis and epithelial-mesenchymal transition (EMT). Twist-1 is essential for the differentiation and specification of mesoderm-derived tissues and hematopoietic stem cells. In hematopoiesis, Twist-1 plays an important role in maintaining the bone marrow niche to support normal hematopoiesis. In human tumorigenesis, Twist-1 is overexpressed and promotes EMT, a key process in the metastases and drug resistance. In addition, recent evidence indicates that Twist-1-Bmi1 axis confers acute myeloid leukemia (AML), cell self-renewal and apoptosis resistance which highlights the importance of the Twist1-Bmi1 axis in the regulation of self-renewal in both normal hematopoietic and leukemia stem cells (LSCs). The hypothesis of the current study states that dysregulation of Twist-1 is implicated in the pathogenesis of various hematological malignancies, AML. This study demonstrates the efficacy of nanoparticle delivery using hyaluronic-acid conjugated mesoporous silica nanoparticles (MSN-HA) as an intracellular delivery mechanism for siRNA designed to knock down Twist-1 (siTwist-1). The nanoparticle is designed for tumor stem cell specificity as its HA component exclusively targets LSCs through their native ligand, CD44. In addition, the nanoparticles' electrostatically bonded polyethylene (PEI) coat protects the siRNA from nuclease degradation. Using siRNA nanotechnology, previous studies demonstrated the ability to target and silence cytoplasmic Twist-1 mRNA and re-sensitize cancer cells to conventional chemotherapeutic agents in solid tumor models. In this study, we demonstrate the efficacy of this nanoparticle siRNA technology on the knockdown of Twist-1 in the AML cell line, KG1a, and the consequent cascading effect of upregulating the tumor suppressor genes and downregulating stemness genes. Our data indicate that Twist-1 promotes leukemia cell growth and colony-forming units (CFU) through the Twist/c-MPL axis, and knockdown of Twist1 inhibits tumor growth and reduce the number of CFUs. Our Results also showed that Twist-1 interacts with Runt domain of Runx-1, and c-MPL, reported to be negatively regulated by RUNx-1. Thus, nanotechnology which combines CD44 targeting and Twist Knockdown, has shown promising results for LSCs targeting, mitigating metastasis in AML. Further investigations of the role of Twist HSC and bone marrow niche will provide more insight into strategic management and treatment for leukemic stem cells. Citation Format: Ebtesam Nafie, Angelina Flores, Idoroenyi Amanam, Ruining Wang, Jeffrey Zink, Lucy Ghoda, Guido Marcucci, Carlotta Glackin. Twisting stemness in AML using nanoparticle as a delivery system for siRNA targeting Twist [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-225.
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