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.