TY - JOUR
T1 - The emerging role of d-2-hydroxyglutarate as an oncometabolite in hematolymphoid and central nervous system neoplasms
AU - Rakheja, Dinesh
AU - Jeffrey Medeiros, L.
AU - Bevan, Scott
AU - Chen, Weina
PY - 2013
Y1 - 2013
N2 - Approximately 20% of unselected cases and 30% cytogenetically diploid cases of acute myeloid leukemia (AML) and 80% of grade II-III gliomas and secondary glioblastomas carry mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. IDH1/2 mutations prevent oxidative decarboxylation of isocitrate to a-ketoglutarate (a-KG) and modulate the function of IDH (neomorphic activity) thereby facilitating reduction of a-KG to D-2-hydroxyglutarate (D-2HG), a putative oncometabolite. D-2HG is thought to act as a competitive inhibitor of α-KG-dependent dioxygenases that include prolyl hydroxylases and chromatin-modifying enzymes. The end result is a global increase of cellular DNA hypermethylation and alterations of the cellular epigenetic state, which has been proposed to play a role in the development of a variety of tumors. In this review, we provide an update on potential molecular mechanisms linking IDH1/2 mutations and the resulting oncometabolite, D-2HG, with malignant transformation. In addition, in patients with AML and glioma we focus on the associations between IDH1/2 mutations and clinical, morphologic, cytogenetic, and molecular characteristics.
AB - Approximately 20% of unselected cases and 30% cytogenetically diploid cases of acute myeloid leukemia (AML) and 80% of grade II-III gliomas and secondary glioblastomas carry mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. IDH1/2 mutations prevent oxidative decarboxylation of isocitrate to a-ketoglutarate (a-KG) and modulate the function of IDH (neomorphic activity) thereby facilitating reduction of a-KG to D-2-hydroxyglutarate (D-2HG), a putative oncometabolite. D-2HG is thought to act as a competitive inhibitor of α-KG-dependent dioxygenases that include prolyl hydroxylases and chromatin-modifying enzymes. The end result is a global increase of cellular DNA hypermethylation and alterations of the cellular epigenetic state, which has been proposed to play a role in the development of a variety of tumors. In this review, we provide an update on potential molecular mechanisms linking IDH1/2 mutations and the resulting oncometabolite, D-2HG, with malignant transformation. In addition, in patients with AML and glioma we focus on the associations between IDH1/2 mutations and clinical, morphologic, cytogenetic, and molecular characteristics.
KW - Acute myeloid leukemia
KW - Glioma
KW - IDH mutation
KW - NPM1 mutation
UR - http://www.scopus.com/inward/record.url?scp=84890840359&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890840359&partnerID=8YFLogxK
U2 - 10.3389/fonc.2013.00169
DO - 10.3389/fonc.2013.00169
M3 - Review article
C2 - 23847760
AN - SCOPUS:84890840359
SN - 2234-943X
VL - 3 JUL
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 00169
ER -