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IDH1 and IDH2 mutations lead to “biochemical gain of function” • IDH, Isocitrate dehydrogenase (IDH1 =cytoplasmic; IDH2 = mitocondrial): NADPdependent enzyme that catalyze the oxidative decarboxilation of isocitrate to α- ketoglutarate, with concomitant production of NADPH. Isocitrate NADP IDH1 IDH2 NADPH α-ketoglutarate NADPH IDH1 R132 IDH2 R172 2-hydroxyglutarate NADP Mutated proteins harbour a new enzyma5c ac5vity: produc5on and accumula5on of 2HG,a rare metabolite normally present at very low levels in healthy cells Yan H et al. NEJM 2009; 360:765-9 Gross S et al, JEM, 2010; 207:339
 Reduc5on of NADPH and glutathione and increase of ROS  Reduc5on of aKG, that normally ac5vate proline hydroxylase that inac5vate HIF1a, and consequently increasing in HIF1a and its associated target Homozygous missense muta5ons have not been iden5fied: the WT protein is necessary to produce NADPH Abdel‐Wahab  and Levine, JEM 2010,207‐4, 677‐680
Page 1 and 2: Le nuove mutazioni oltre JA
Page 3: NADP+-dependent isocitrate dehydrog
Page 7 and 8: Somatic mutations of IDH1 and IDH2
Page 9 and 10: Tefferi et al., Leukemia (2010) 24,
Page 11 and 12: Clinical correlates and progn
Page 13 and 14: Oh ST et al, Blood. 2010
Page 15 and 16: ID DG JAK2V617F IDH LNK 1 2 PMF AML
Page 17: Dr.ssa ElisabGa Antonioli Dr.

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