Aberrant oxidative metabolism selects for TET2 -deficient hematopoietic stem and progenitor cells - PubMed
6 hours ago
- #oxidative metabolism
- #TET2 deficiency
- #clonal hematopoiesis
- The study explores the role of metabolism in the selective expansion of TET2-deficient hematopoietic stem and progenitor cells (HSPC) in clonal hematopoiesis (CH).
- Loss of Tet2 in murine HSPC leads to overexpression of glycolysis and oxidative phosphorylation genes, increasing oxidative metabolism via an enlarged mitochondrial network while maintaining a normal redox state.
- Compound loss of glucose-6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway (PPP), increases reactive oxygen species and impairs the fitness of Tet2-deficient HSPC.
- Aberrant oxidative metabolism is also observed in human CH and clonal cytopenia of unknown significance (CCUS), indicating a conserved mechanism.
- The study identifies the PPP as a crucial compensatory pathway that maintains the selective advantage of TET2-deficient HSPC, highlighting targetable metabolic vulnerabilities.