Abstract Epithelial-mesenchymal transition (EMT) is an evolutionarily conserved developmental program frequently co-opted in solid tumors to drive metastasis and therapy resistance. Whether analogous transcriptional and metabolic machinery operates in blood cancers has remained unexplored. Here, we demonstrate—for the first time—that drug-tolerant persister (DTP) cells in mantle cell lymphoma (MCL), a lethal non-Hodgkin’s lymphoma, exploit an EMT-like program distinct from cancer stem cell pathways to establish stable resistance to BTK inhibitors (BTKi) and anti-CD19 CAR T-cell therapy. Using pirtobrutinib, a clinically approved non-covalent BTKi, we established a reproducible, non-stochastic DTP cell model in MCL. Integrated RNA sequencing and ultra-high-resolution metabolomics revealed that therapeutic pressure triggers a striking morphogenetic switch: proliferative lymphoma cells transform into enlarged, quiescent “Giant cells” characterized by profound dedifferentiation and loss of B-cell identity (including CD19). Upon drug withdrawal, Giant cells rapidly revert to proliferative, normal-sized progeny, exposing a previously unrecognized reversible plasticity in hematologic malignancies. Mechanistically, DTP cells rewire the TCA cycle by engaging the malate-aspartate shuttle, sustaining cytoplasmic anabolic metabolism during drug exposure. Drug removal abruptly shifts the TCA cycle to catabolic mode, fueling re-entry into the cell cycle. This metabolic switch orchestrates global transcriptomic reprogramming with elevated acetyl-CoA levels, which stabilizes the core EMT transcription factor SNAI1 via non-histone protein acetylation. Remarkably, acetylated SNAI1 translocated to nucleoli, driving ribosome biogenesis (marked by fibrillarin upregulation) —a hallmark less studied in conventional EMT of epithelial cancers. Perturbing ATP-citrate lyase (ACL), SNAI1, or inhibiting ribosome biogenesis disrupts this axis: ACL/SNAI1 blockade accelerates exit from the Giant cell state, whereas suppression of ribosome biogenesis leads to DTP cell death. In therapy-refractory MCL patients, DTP cells can be dynamically abundant, exceeding classic minimal residual disease—and detectable by immunohistochemistry, metabolic imaging, and single-cell RNA sequencing. Thus, unlike solid tumors where EMT primarily enables invasion, blood cancer cells repurpose this ancient developmental program for metabolic resilience and immune evasion. Our work establishes that an EMT-like network, orchestrated by metabolic reprogramming and nucleolar SNAI1-driven ribosome biogenesis, governs DTP cell fate in MCL. Targeting this axis—particularly ribosome biogenesis—offers a transformative strategy to eradicate persister cells and overcome resistance to BTKi and CAR T-cell therapy. Citation Format: Wei Wang, Yang Liu, Heng-Huan Lee, Fangfang Yan, Yijing Li, Yue Fei, Ching-Fei Li, Michael Wang. EMT-like reprogramming defines drug-tolerant persister cell plasticity in mantle cell lymphoma abstract. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7 (3Suppl): Abstract nr A018.
Wang et al. (2026) studied this question.