TET2 as an epigenetic signaling hub: interactome networks, metabolic control and therapeutic vulnerabilities in hematologic malignancies

Abstract Ten–eleven translocation 2 (TET2) is an essential epigenetic regulator that orchestrates hematopoietic stem cell self-renewal and lineage commitment through oxidation of 5-methylcytosine and subsequent remodeling of the DNA methylation landscape. Recurrent TET2 mutations represent one of the earliest and most prevalent genetic alterations in clonal hematopoiesis in a broad spectrum of myeloid and lymphoid malignancies. TET2 has traditionally been regarded as a DNA demethylase, emerging evidence indicates that it also functions as a chromatin-associated scaffold to determine cell fate by coordinating metabolic signals, chromatin regulators and transcription factors, etc. Loss of TET2 disrupts these networks, promoting aberrant stemness, impaired differentiation and leukemogenic transformation. Here, we integrate current knowledge of its epigenetic roles, catalytic and non-catalytic functions, metabolic controls, post-translational modifications and regulatory interactomes in both normal and malignant hematopoiesis. We further highlight context-specific therapeutic vulnerabilities created by TET2 deficiency and discuss strategies to restore or exploit TET2-dependent epigenetic states. This integrated framework positions TET2 as a central epigenetic signaling hub and delineates opportunities for precision therapy in hematologic malignancies.