CD33 targeted EzH1 regulated nanotherapy epigenetically inhibits fusion oncoprotein (AML1-ETO) rearranged acute myeloid leukemia in both in vitro and in vivo Patient Derived Xenograft models

Acute myeloid leukemia (AML) is one of the most heterogeneous myeloid malignancies wherein the genetic and epigenetic markers contribute to AML pathogenesis. Genetic regulators such as fusion oncogene, AML1-ETO, controls AML pathogenesis and contribute to ∼20 % AML cases. The epigenetic factors such as histone methyltransferase, EzH1, is highly overexpressed in AML and regulate AML proliferation. The EzH1 inhibition overturns disease pathology but available therapeutics exhibit off-target toxicity and frequent relapses which lack AML targeting ability. Here, we have prepared CD33-targeted S30 aptamer-functionalized human serum albumin nanoparticles for EzH1 siRNA delivery for the first time as anti-AML therapeutics in vitro, in vivo nude mice and patient-derived xenografts models. The S30 aptamer functionalization enhanced the transfection efficiency and cytotoxicity through apoptosis and increased the reduction of c-Kit⁺ leukemia cells along with upregulation of myeloid differentiation markers, CD11b and Gr-1, in nude mice AML xenografts. The nanoparticles exhibited the similar efficacy with improved survival outcome in patient-derived xenografts. Furthermore, we for the first time showed that transcription factor, C-Myb, directly regulates EzH1 through promoter binding which regulates the functional characteristics of in vivo AML. The present nanotherapy abrogates C-Myb–EzH1 crosstalk mediated AML pathogenesis and holds future translation potential as novel anti-AML therapeutics.