Authors
Mohd Ayoub, Devangi Ghosh, Vikas Kumar Sahu, Liku Biswal, Pankaj Malhotra, Surajit Karmakar, Subhasree Roy Choudhury
Published in
Acta biomaterialia. Sep 20, 2026. Epub Sep 20, 2026.
Abstract
Acute Myeloid Leukemia (AML) is a prevalent and aggressive hematologic cancer driven by leukemic stem cells and immune evasion. Among its subtypes, Mixed Lineage Leukemia-AF9 (MLL-AF9)- rearranged AML is exceptionally lethal, with B-cell lymphoma 2 (Bcl2), a key anti-apoptotic protein, supporting leukemic survival and immune dysfunction. Targeting Bcl2 in this context is crucial for dismantling oncogenic circuits and restoring immune activity. Here, we have synthesized, de novo, IL-3 receptor alpha chain (IL-3Rα, commonly known as cluster of differentiation 123 or CD123) targeted aptamer-tethered liposomal nanocarriers (CD123-si-Bcl2@LNPs) encapsulating Bcl2 siRNA (CD123-si-Bcl2@LNPs) for selective AML targeting, survival disruption, and immune restoration. Mechanistic studies established a previously uncharacterized signaling axis wherein the MLL-AF9 fusion oncoprotein induces the overexpression of the transcription factor c-Myb. This induced c-Myb binds directly to the Bcl2 promoter, upregulating Bcl2 expression and enhancing both STAT3 expression and its Ser727 autophosphorylation. Consequently, this pathway amplifies IL-6-driven immunosuppression and dampens NK and CD8⁺ T cell responses. Nanocomposite-mediated disruption of this specific axis successfully reversed these oncogenic and immunosuppressive signals. Therapeutic efficacy was evaluated using a patient-derived xenograft (PDX) model, generated by retroviral MLL-AF9 overexpression in CD34⁺/CD38⁻ sorted leukemic stem cells from AML patients and engraftment into NOD/SCID mice. CD123-si-Bcl2@LNPs significantly reduced leukemic burden in vivo. Bcl2 siRNA encapsulated liposomal nanoparticles demonstrated robust Bcl2 knockdown, apoptosis induction, and impaired leukemic self-renewal across in vitro and in vivo models. Post-treatment immune profiling revealed enhanced NK cell (CD56⁺) expression and reversal of T cell exhaustion, with CD8⁺ T cell activation marked by downregulation of CTLA-4. Differentiation marker analysis revealed decreased CD45+ and c-KIT+ expression, accompanied by an upregulation of the myeloid monocyte differentiation marker CD11b, indicating myeloid maturation and a reduction in leukemic stemness. This dual-action therapeutic strategy simultaneously targets survival and immune evasion pathways in MLL-AF9-positive AML cells by the treatment of CD123-si-Bcl2@LNPs, offering a promising, precision-guided nano-immunotherapeutic strategy for future translational potential for MLL-AF9-positive acute myeloid leukemia. STATEMENT OF SIGNIFICANCE: •The CD123 aptamer-targeted liposomal nanocarrier facilitates precise siRNA delivery in acute myeloid leukemia (AML), significantly enhancing the transfection efficiency and stability of Bcl2 siRNA. •siRNA nanotherapy reveals a novel immune-evasion axis involving c-Myb, Bcl2, and STAT3 axis which is critical for the progression of AML. •Targeted silencing of Bcl2 disrupts the survival networks of leukemic stem cells. •Nano-immunotherapy revitalizes the antitumor activity of natural killer (NK) cells and CD8⁺ T-cells. •Liposomal siRNA therapy effectively suppresses MLL-AF9 leukemia in NOD/SCID patient-derived xenograft (PDX) mouse models.
PMID:
42764087
Bibliographic data and abstract were imported from PubMed on 21 Sep 2026.
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