Abstract
An essential feature of acute myeloid leukemia (AML) is the profound block to differentiation exhibited by leukemic cells. This AML-associated arrest in the normal process of cellular differentiation is not observed in more chronic forms of leukemia. Chronic forms of leukemia and lymphoma are marked by the increased propensity to enter the cell cycle as the malignant cells move to more mature states of differentiation and the increased resistance to apoptosis these cells exhibit. Considerable recent evidence has suggested that profound epigenetic remodeling occurs as either a result or a cause of cellular differentiation. Altered DNA methylation has now been established as a hallmark of acute leukemia and yet very little is known concerning the mechanisms through which this occurs. In 2010, in collaboration with others, we found that neomorphic mutations of the citrate metabolism genes IDH1 and IDH2 induce DNA hypermethylation and impair differentiation in hematopoietic cells. IDH mutations create a block to DNA and histone demethylation as a result of the production of 2-hydroxyglutarate (2HG). 2HG acts as a competitive inhibitor of α-ketoglutarate-dependent enzymes. The epigenetic effects of 2HG are caused in part though inhibition of TET2, a DNA demethylase enzyme also mutated in leukemia. IDH 1/2- and TET2-mutant primary AML cells displayed a similar defect in epigenetic programming consisting of global hypermethylation and a gene-specific methylation signature. This work identifies IDH1/2- and TET2-mutant leukemias as a biologically distinct disease subtype, and links cancer metabolism with epigenetic control of gene expression. The implications of this work and the identification of additional metabolic genes involved in epigenetic deregulation in leukemia will be discussed.
Thompson:NIH: Research Funding; Keystone Symposia: Consultancy; NCI: Research Funding; Damon Runyon : Research Funding; Ludwig: Membership on an entity’s Board of Directors or advisory committees; HHMI: Membership on an entity’s Board of Directors or advisory committees; Merck: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; Agios: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; MSKCC: Employment; Pfizer: Patents & Royalties; BMS: Patents & Royalties; Repligen: Patents & Royalties.
Author notes
Asterisk with author names denotes non-ASH members.
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