CD123 Targeted Epigenetic Nanotherapy for Fusion Oncoprotein MLL-AF9 Rearranged Acute Myeloid Leukemia in Preclinical and Patient Derived Xenograft Models.

Acute Myeloid Leukemia (AML) is a heterogeneous hematological malignancy with an altered bone marrow microenvironment sheltering leukemic stem cells (LSCs). LSCs are characterized as self-renewing and highly proliferative cancer stem cells and accumulate abnormal genetic and epigenetic factors contributing to their uncontrolled proliferation. Chromosomal translocation t(9;11)(p22;q23) forms fusion oncoprotein, MLL-AF9, and regulates the transcription factor, C-Myb, which is highly expressed in AML. C-Myb regulates polycomb protein, EzH2, but this is still unexplored in MLL-AF9-induced AML, which highly expresses CD123. The active targeting with epigenetic regulation of EzH2 in MLL-AF9-rearranged AML can provide novel translational potential for anti-AML therapeutics. So, CD123-targeted delivery of EzH2 siRNA is hypothesized through ZW25 aptamer-functionalized human serum albumin nanoparticles (si-EzH2@HNPs@ZW25) for enhanced anti-AML therapeutics in MLL-AF9-induced in vitro and in vivo AML models. si-EzH2@HNPs@ZW25 exhibit superior therapeutic efficacy under MLL-AF9-induced athymic xenografts with enhanced suppression of c-Kit+ LSCs, and stimulation of myeloid-specific differentiation markers, CD11b and Gr-1. si-EzH2@HNPs@ZW25 increased the survival of CD34+CD38- AML patient-derived xenograft mice and augmented the suppression of c-Kit+ LSCs and stimulation of CD11b and Gr-1. In MLL-AF9 AML, C-Myb directly regulates EzH2 through promoter binding wherein si-EzH2@HNPs@ZW25 disrupt this functional crosstalk in AML revealingfuture translational potential of si-EzH2@HNPs@ZW25 as AML therapy.