Receptor Reexpression after Hypermethylation: Novel Targets for Inhibitors and Antibody-Drug Conjugates in ALL

Despite improved overall prognosis, the treatment of high-risk acute lymphoblastic leukemia (ALL) remains challenging due to the toxicity of intensive polychemotherapy and the limited efficacy of antibody-targeted therapies beyond cluster of differentiation 20 and 22 (CD20 and CD22). ALL is driven not only by genetic alterations but also by profound epigenetic dysregulation, including promoter hypermethylation that also silences surface receptor genes. This epigenetic repression can reduce the efficacy of targeted immunotherapies and contribute to relapse. Epigenetic reprogramming with DNA demethylating agents (e.g., decitabine) has the potential to restore the expression of key B cell receptors such as CD19 or CD20, as well as other therapeutically relevant target antigens on the cell surface, thus enhancing the susceptibility of leukemia cells to antibody-based therapies. In addition to new generations of bispecific antibodies and advanced CAR-T cell constructs, novel antibody-drug conjugates (ADCs) are increasingly coming into focus. The sequential application of DNA methylation inhibitors followed by ADC or inhibitor treatment represents an innovative approach that simultaneously restores tumor suppressor function, enhances leukemia immunogenicity, and expands the therapeutic window of receptor-targeted therapies. We investigated the hypothesis that several hypermethylated genes encoding cell surface proteins accessible to immunotherapy exist in acute lymphoblastic leukemia (ALL). Our review provides a comprehensive analysis of hypermethylated cell surface markers for ALL and the underlying epigenetic reprogramming after demethylation. We propose that the integration of epigenetic therapies into existing immuno-oncology treatment regimens could substantially improve treatment efficacy and open new avenues to overcome resistance mechanisms in ALL.