Transcriptional remodeling shapes therapeutic vulnerability to necroptosis in acute lymphoblastic leukemia

• Published in: Blood Vol. 146; no. 7; pp. 861 - 873
• Main Authors: Saorin, Anna, Dehler, Anna, Galvan, Bartimée, Steffen, Fabio, Ray, Marine, Lu, Dong, Yu, Xin, Kim, James, Drakul, Aneta, Kisele, Samanta, Wang, Jin, Bourquin, Jean-Pierre, Bornhauser, Beat C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.08.2025
• Subjects: Animals; Cell Line, Tumor; Gene Expression Regulation, Leukemic - drug effects; Histone Deacetylase Inhibitors - pharmacology; Humans; Mice; Necroptosis - drug effects; Necroptosis - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism; Transcription, Genetic - drug effects
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2025028938

•Transcriptional dependency of RIPK1-driven necroptosis is a key regulatory mechanism in ALL, modulated by SP1, p300, and HDAC2.•Combination of SMAC mimetics and HDAC inhibitors can be a clinically relevant option for resensitizing resistant ALL toward cell death. [Display omitted] Insufficient eradication of cancer cells and survival of drug tolerant clones are major relapse driving forces. Underlying molecular mechanisms comprise activated prosurvival and antiapoptotic signaling, leading to insufficient apoptosis and drug resistance. The identification of programmed cell death pathways alternative to apoptosis opens up possibilities to antagonize apoptosis escape routes. We have earlier shown that acute lymphoblastic leukemia (ALL) harbors a distinct propensity to undergo cell death by receptor-interacting protein kinase 1 (RIPK1)−dependent necroptosis, activated by small-molecule second mitochondria-derived activators of caspase (SMAC) mimetics. Despite demonstrated safety and tolerability of SMAC mimetics in clinical trials, their efficacy as single agent seems still limited, highlighting the need for combinatorial treatments. Here, we investigate so far unexplored regulatory mechanisms of necroptosis and identify targets for interference to augment the necroptotic antileukemia response. Ex vivo drug response profiling in a model of the bone marrow microenvironment reveals powerful synergy of necroptosis induction with histone deacetylase (HDAC) inhibition. Subsequent transcriptome analysis and functional in vivo CRISPR screening identify gene regulatory circuitries through the master transcription regulators specificity protein 1 (SP1), p300, and HDAC2 to drive necroptosis. Although deletion of SP1 or p300 confers resistance to necroptosis, loss of HDAC2 sensitizes cells to RIPK1-dependent cell death by SMAC mimetics. Consequently, our data inform strong in vivo antileukemic activity of combinatorial necroptosis induction and HDAC inhibition in patient-derived human leukemia models. Thus, transcriptional dependency of necroptosis activation is a key regulatory mechanism that identifies novel targets for interference, pointing out a strategy to exploit alternative nonapoptotic cell death pathways to eradicate resistant disease. While the majority of children and adolescents with acute lymphoblastic leukemia (ALL) can be cured with chemoimmunotherapy regimens, drug resistance remains a significant cause of treatment failure, highlighting the need for new therapeutic strategies. Saorin et al used functional genomic approaches along with a large cohort of primary B-ALL and T-ALL specimens and patient-derived xenograft models to uncover regulatory mechanisms of necroptosis. They show that interference with transcriptional regulation enhances RIPK1-dependent necroptosis and leukemic cell death. These findings suggest that combining necroptosis induction with histone deacetylase inhibition may offer a promising strategy to overcome treatment resistance in ALL.