3.0
IDH-TET in AML
Pathway ID: SIGNOR-AML-IDH_TET
Description: Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate(α-KG), which is required for activity of the Methylcytosine Dioxygenase (TET, Ten-Eleven-translocation) enzyme. A group of Acute Myeloid Leukemia (AML) patients (>15%), with normal cytogenetics, harbor missense mutations in either of the two isocitrate dehydrogenase genes, IDH1 or IDH2. The mutated enzymes acquire a neomorphic activity and produce the onco-metabolite 2-hydroxyglutarate (2HG). As a consequence, the TET2 DNA dioxygenase is catalitically inactivated and cannot modulate DNA de-methylation and expression of a number of genes. Loss of function mutations in TET2 are frequently detected in hematopoietic malignancies, in particular AML (~15 – 20%). Some AML-associated TET2 mutations disrupt its binding to the Wilms Tumor transcription factor (WT1). WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of its target genes.Mutations in IDH, TET and WT1 are mutually exclusive since they function along the same pathway. WT1 is overexpressed in a number of of AML patients and its increased levels are associated with resistance to therapy, a higher incidence of relapse, and poor overall survival. Increased glucose levels impede AMPK-mediated phosphorylation of TET2 at serine 99, thus destabilizating TET2. This links diabetes to cancer, metformin and antidiabetic drugs to cancer prevention.PMID: 27252512, 21723201, 19657110, 30022161
Curated by: miannu
Description: Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate(α-KG), which is required for activity of the Methylcytosine Dioxygenase (TET, Ten-Eleven-translocation) enzyme. A group of Acute Myeloid Leukemia (AML) patients (>15%), with normal cytogenetics, harbor missense mutations in either of the two isocitrate dehydrogenase genes, IDH1 or IDH2. The mutated enzymes acquire a neomorphic activity and produce the onco-metabolite 2-hydroxyglutarate (2HG). As a consequence, the TET2 DNA dioxygenase is catalitically inactivated and cannot modulate DNA de-methylation and expression of a number of genes. Loss of function mutations in TET2 are frequently detected in hematopoietic malignancies, in particular AML (~15 – 20%). Some AML-associated TET2 mutations disrupt its binding to the Wilms Tumor transcription factor (WT1). WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of its target genes.Mutations in IDH, TET and WT1 are mutually exclusive since they function along the same pathway. WT1 is overexpressed in a number of of AML patients and its increased levels are associated with resistance to therapy, a higher incidence of relapse, and poor overall survival. Increased glucose levels impede AMPK-mediated phosphorylation of TET2 at serine 99, thus destabilizating TET2. This links diabetes to cancer, metformin and antidiabetic drugs to cancer prevention.PMID: 27252512, 21723201, 19657110, 30022161
Curated by: miannu
