2. Academic Validation
  3. Scaffolding-dependent CASP1 constrains excessive cell-intrinsic inflammatory signaling in leukemia

Scaffolding-dependent CASP1 constrains excessive cell-intrinsic inflammatory signaling in leukemia

  • Cell Chem Biol. 2026 Jan 15;33(1):59-73.e10. doi: 10.1016/j.chembiol.2025.12.002.
Emma E Uible 1,  Issac Choi 1,  Courtnee A Clough 2,  Aishlin Hassan 2,  Annabelle J Anandappa 3,  Julianna Fisher 1,  Bibek Karki 4,  Kathleen Hueneman 2,  Kwangmin Choi 2,  Eric J Vick 3,  William Seibel 5,  Kenneth D Greis 6,  Lynn Lee 7,  Courtney Jones 8,  Timothy M Chlon 8,  Jorge Henao-Mejia 9,  Chandrashekhar Pasare 10,  John T Cunningham 6,  Andrew G Volk 8,  Daniel T Starczynowski 11
Affiliations

Affiliations

  • 1 Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
  • 2 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
  • 3 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, OH, USA; Division of Hematology & Oncology, University of Cincinnati, Cincinnati, OH, USA; University of Cincinnati Cancer Center, Cincinnati, OH, USA.
  • 4 Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.
  • 5 Division of Oncology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
  • 6 Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA; University of Cincinnati Cancer Center, Cincinnati, OH, USA.
  • 7 University of Cincinnati Cancer Center, Cincinnati, OH, USA; Division of Oncology, Cincinnati Children's Hospital, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
  • 8 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, OH, USA; University of Cincinnati Cancer Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
  • 9 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
  • 10 Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA; Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
  • 11 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, OH, USA; University of Cincinnati Cancer Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA. Electronic address: [email protected].
PMID: 41500224 DOI: 10.1016/j.chembiol.2025.12.002
Abstract

Caspase-1 (CASP1) is best known for regulating IL-1β processing and pyroptosis; however, its role in leukemia has not been clearly defined. Here, we show that loss of CASP1 impairs leukemic cell growth, drives differentiation, and reduces leukemic burden in vivo, independent of its CASP1 protease activity. Instead, CASP1 functions as a scaffolding hub, controlling nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling via its interaction with raptor (RPTOR), a component of mTORC1. Deletion of CASP1 or disruption of its CARD domain induces excessive NF-κB activity and impairs leukemic cell function. We further developed a proteolysis-targeting chimera (PROTAC) degrader that selectively depletes Pro-CASP1 and suppresses leukemic cells. These findings reveal CASP1 as a regulator of mTORC1-NF-κB signaling in leukemia and highlight its scaffolding activity as a therapeutic vulnerability.

Keywords

AML; CASP1; NF-κB; RAPTOR; inflammasome; mTOR.

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