Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis

Cell chemical biology 2026 Open access

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Authors: Peter Geon Kim, Christopher A. Hergott, Aidan P. Miller, Amy Deik, Meaghan Boileau, Kevin Bullock, Kerry A. Pierce, Angelina H. Choy, Wesley Shin, Marie McConkey, Justin Loke, Birgitta Ryback
+11 more Michael Trinh, Justine C. Rutter, Hong Yue, Hojong Yoon, Paul Park, Shourya S. Roy Burman, Matthew G. Vander Heiden, Eric S. Fischer, Scott A. Armstrong, Clary B. Clish, Benjamin L. Ebert
DOI: 10.1016/j.chembiol.2026.01.006
Cited by: 2
References: 79

Abstract

hematopoietic stem-progenitor cells (HSPCs) to elucidate the basis of Tet2 KO inflammation. We uncover a metabolic circuit by which Tet2 restrains O-linked N-acetylglucosamine (O-GlcNAc) glycosyltransferase (Ogt), a Tet2 binding partner and metabolic sensor. Tet2 loss disrupts this inhibitory Tet2-Ogt interaction, and dysregulated Ogt facilitates widespread H3K4 trimethylation including lipid-related gene loci and inflammatory lipid droplet formation. We identified that ATP citrate lyase (Acly) is decorated with O-GlcNAc and is a critical node for lipid accumulation and inflammation in Tet2 KO. These findings reveal that Tet2 suppresses inflammation by gating nutrient-responsive chromatin remodeling and nominate metabolic interventions to restrain inflammatory disease in TET2-mutant clonal hematopoiesis.

Fields of Study & Subjects

Acute Myeloid Leukemia Research Complement system in diseases Acute Lymphoblastic Leukemia research

Publication details

Journal / source
Cell chemical biology
Publisher
Elsevier BV
Volume
33
Issue
2
Pages
183–197.e9
Publication date
1 February 2026
Language
EN