Antigen-directed p53 restoration in TP53-mutated myeloid neoplasms: a hypothesis and theory perspective

TP53-mutated myeloid neoplasms, including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), remain among the hardest-to-treat hematologic malignancies, with short survival despite hypomethylating agents +/- venetoclax, and allogeneic transplantation. Despite encouraging early-phase data, Phase 3 trials of mutant-p53 reactivators to date have not yet translated into clear, practice-changing survival benefits, highlighting a need to explore complementary strategies that aim to directly restore wild-type p53 function in the leukemic niche. Building on clinical experience with the adenoviral p53 product (rAd-p53) in solid tumors, where intratumoral rAd-p53 achieves high cumulative response rates with manageable toxicity, we investigate the feasibility of translating p53 replacement into select TP53-mutated myeloid neoplasms using antigen-directed delivery systems. Advances in AML surface proteomics and immunotherapy identify many antigens of interest, in particular, CD33, CD123, and CD209, as internalizing myeloid antigens that are broadly expressed on leukemic blasts and stem/progenitor cells. In parallel, emerging data on in vivo gene delivery via lipid nanoparticles (LNP) and adenovirus platforms that are capable of efficient marrow transduction demonstrate that systemic gene transfer to hematopoietic compartments is feasible. We outline a framework in which CD33-, CD123-, and CD209-directed mRNA/LNP systems or leukemia-adapted rAd-p53 vectors could potentially be used to restore wild-type TP53 in TP53-mutant myeloid clones and discuss key preclinical questions in xenograft models. We acknowledge that the strategy is built on converging but largely indirect lines of evidence rather than direct experimental data in TP53-mutated AML/MDS, and we explicitly discuss key preclinical validation requirements and biological barriers, including dominant-negative stoichiometry, liver sequestration, and by conceivable toxicities, that must be systematically addressed before clinical translation.