Details

Autor(en) / Beteiligte

• Fortin, Jerome
• Chiang, Ming-Feng
• Meydan, Cem
• Foox, Jonathan
• Ramachandran, Parameswaran
• Leca, Julie
• Lemonnier, François
• Li, Wanda Y
• Gams, Miki S
• Sakamoto, Takashi
• Chu, Mandy
• Tobin, Chantal
• Laugesen, Eric
• Robinson, Troy M
• You-Ten, Annick
• Butler, Daniel J
• Berger, Thorsten
• Minden, Mark D
• Levine, Ross L
• Guidos, Cynthia J
• Melnick, Ari M
• Mason, Christopher E
• Mak, Tak W

Titel

Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2023-01, Vol.120 (4), p.e2208176120-e2208176120

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Mutations in , and are recurrently observed in myeloid neoplasms. and encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, , , and mutations may converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have distinct, and even opposite, effects on hematopoietic stem and progenitor cells in genetically engineered mice. Epigenetic and single-cell transcriptomic analyses revealed that and loss-of-function have divergent consequences on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregulation in cells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects of and mutations, providing support for the optimization of genotype-specific therapies.