Transcriptional remodeling shapes therapeutic vulnerability to necroptosis in acute lymphoblastic leukemia.
| Title: | Transcriptional remodeling shapes therapeutic vulnerability to necroptosis in acute lymphoblastic leukemia. |
|---|---|
| Authors: | Saorin A; Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland.; Dehler A; Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland.; Galvan B; Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland.; Steffen F; Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland.; Ray M; Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland.; Lu D; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX.; Yu X; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX.; Kim J; Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland.; Drakul A; Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland.; Kisele S; Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland.; Wang J; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.; Bourquin JP; Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland.; Bornhauser BC; Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland. |
| Source: | Blood [Blood] 2025 Aug 14; Vol. 146 (7), pp. 861-873. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2021- : [New York] : Elsevier; Original Publication: New York, Grune & Stratton [etc.] |
| MeSH Terms: | Precursor Cell Lymphoblastic Leukemia-Lymphoma*/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma*/pathology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma*/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma*/metabolism ; Necroptosis*/drug effects ; Necroptosis*/genetics ; Gene Expression Regulation, Leukemic*/drug effects ; Transcription, Genetic*/drug effects; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Sp1 Transcription Factor/genetics ; Sp1 Transcription Factor/metabolism ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Animals ; Mice ; Cell Line, Tumor |
| Abstract: | Abstract: 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.; (© 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.) |
| Comments: | Comment in: Blood. 2025 Aug 14;146(7):774-775. doi: 10.1182/blood.2025029478.. (PMID: 40811006) |
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| Grant Information: | R01 CA268518 United States CA NCI NIH HHS |
| Substance Nomenclature: | EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases); EC 2.7.11.1 (RIPK1 protein, human); 0 (Sp1 Transcription Factor); 0 (Histone Deacetylase Inhibitors); 0 (SP1 protein, human) |
| Entry Date(s): | Date Created: 20250513 Date Completed: 20250825 Latest Revision: 20260112 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12783532 |
| DOI: | 10.1182/blood.2025028938 |
| PMID: | 40359431 |
| Database: | MEDLINE |
Journal Article