Abstract 293: DNMT1 promotes escape from chemotherapy-induced senescence in acute myeloid leukemia

In addition to inducing cell death, chemotherapy can trigger cellular senescence in cancers as a side effect that is typically viewed beneficial for hindering cancer progression. However, acute myeloid leukemia (AML) cells can evade chemotherapy-induced senescence (CIS), leading to therapy failure and disease recurrence. To reduce the risk of AML recurrence, we investigated the mechanisms underlying CIS escape in AML that remain largely elusive. To achieve this, we developed an ex vivo AML recurrence model using primary patient-derived AML cells following exposure to chemotherapy (Ara-C). To minimize potential confounding effects caused by genetic heterogeneity, we utilized single-cell-expanded monoclonal AML populations. These populations were analyzed following CIS escape through integrative transcriptome and DNA methylome profiling. Our analyses revealed that, beside random DNA methylation changes, AML clones gained gene-specific promoter DNA hypermethylation sites associated with transcriptional silencing after CIS escape. This gained transcriptional silencing was conserved across five genetically independent AML specimens, suggesting a shared mechanism underlying AML recurrence after CIS. Using CRISPR-based epigenome-editing tools, we demonstrated that these acquired promoter DNA hypermethylation sites enhanced the survival fitness of AML cells during CIS. To identify the DNA methyltransferase (DNMT) responsible for this epigenetic silencing, we conducted knockdown experiments and identified DNMT1 as the key mediator. Both genetic and pharmacological inhibition of DNMT1 effectively blocked AML cells from escaping CIS. Overall, targeting DNMT1 disrupted CIS escape in AML cells, offering a therapeutic strategy to mitigate the risk of relapse driven by senescence-like leukemia cells. Citation Format: Manna Ahmed,Dharmendra Kashyap,Hannah Kim,Cihangir Duy. DNMT1 promotes escape from chemotherapy-induced senescence in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 293.