Multifunctional nanoparticle-mediated SHARP1 knockdown in MLL-AF6 acute myeloid leukemia [post]

Sameh A. Mohammed, Yang Ju
2021 unpublished
Acute myeloid leukemia (AML) has an extremely poor prognosis and high relapse and fatality rates. We targeted SHARP1 using multifunctional small interfering RNA (siRNA) and bortezomib (BTZ)-loaded cRGD-guided PEGylated cationic liposomal nanoparticles to monitor their antileukemic activity in MLL-AF6 AML cells. Efficient siRNA/BTZ co-delivery by the nanoparticles significantly inhibited cell viability, decreasing clonogenic growth of AML cells and stimulating robust apoptosis. We hypothesized
more » ... at SHARP1 downregulation induced nonfunctional MLL-AF6, DOT1L, MEN1, and LEDGF fusion protein accumulation, preventing MLL-AF complex formation and downregulating RAS-GTP and Bcl-2, consequently triggering autophagy and apoptosis. The BTZ combination substantially augmented therapeutic synergy leading to enhanced autophagic and apoptotic events. Our findings demonstrate a state-of-the-art biodegradable nanoplatform for siRNA/BTZ co-delivery with targeted SHARP1 knockdown, demonstrating a potential therapeutic option for MLL-AF6 AML.
doi:10.21203/rs.3.rs-817454/v1 fatcat:jfugqmkzxzh3pfjshim474yfsi