Roles of IDH1/2 and TET2 mutations in myeloid disorders

Abstract

Although mutated IDH1/2 are clearly established as oncogenes in myeloid cells, the mechanisms underlying their tumorigenic effects are not clear. Much evidence suggests that mutant IDH enzymes exert their effects via inhibition of TET2, but important clinical differences between IDH1-mutant and TET2-mutant hematopoietic disorders suggest that the oncogenic mechanisms of these mutated enzymes may differ. In particular, divergent effects of mutant IDH1/2 and TET2 on DNA damage repair mechanisms have been identified. In this review, we examine mutant IDH1/2 and TET2 in the context of responses to DNA damage and their potential involvement in genomic instability. We also discuss the clinical relevance of these findings and their potential application in novel therapeutic strategies. Mutation of TET family enzymesThe TET family of dioxygenases is highly conserved and contains three members: TET1, -2 and -3. Somatic mutations of TET2 occur in various myeloid disorders, including chronic myelomonocytic leukemia (CMML) (~50 %), myeloid proliferative neoplasm (MPN) (~13 %), MDS (~25 %) and AML (~23 %) [1,2]. TET2 is also mutated in B and T cell lymphoid malignancies, including angioimmunoblastic T cell lymphoma (AITL) [3]. More recently, TET2 mutations have been detected in elderly individuals with clonal hematopoiesis of indeterminate potential, i.e.: individuals with clonal hematopoiesis without identified hematological disease. This indicates that TET2 mutations alone cannot drive leukemogenesis and that additional events probably contribute [4,5]. Interestingly, TET1 and TET3 mutations are rare in human hematological diseases [6]. This predominance of TET2 alterations is not Abstract Mutations of the epigenetic enzymes isocitrate dehydrogenase (IDH) 1 and 2, and the methylcytosine dioxygenase 'ten-eleven translocation 2' (TET2), are common in human myeloid malignancies and drivers of these disorders but the underlying mechanisms remain obscure. This review examines mutant IDH1/2 and TET2 enzymes in the context of responses to DNA damage and their potential involvement in age-related genomic instability. The clinical relevance of these findings and their potential application in novel therapeutic strategies is also discussed.

Epigenetic Function of TET Family, 5-Methylcytosine, and 5-Hydroxymethylcytosine in Hematologic Malignancies

“…In 2009, two reports showed that the chromosomal region 4q24 in human containing TET2 gene frequently underwent microdeletions and copy number-neutral loss-of-heterozygosity (also named uniparental disomy) in myeloid cancers [35, 36]. Additionally, mutant IDH enzymes can exert their effects via inhibition of TET2, resulting in decreased 5-hmC via the oncometabolite 2 HG [83]. Recently, various reports have showed a high frequency of loss-of-function mutation of the TET2 gene in hematologic malignancies, including MDS, MPN, AML, secondary AML, CMML, and so on [34-42].…”

From cellular morphology to molecular and epigenetic anomalies of myelodysplastic syndromes

“…IDH1/2 (isocitrate deshydrogenase 1/2) mutations are closely associated with higher bone marrow blasts, lower neutrophil counts, and unspecific karyotypes . Mutant IDH1/2 can block myeloid differentiation and increase the accumulation of DNA damage in hematopoietic stem cell/myeloid progenitors leading to oncogenic transformation . IDH1/2 mutations vary from 4% to 12% in patients with MDS and are more common in AML .…”

Taking a Bad Turn: Compromised DNA Damage Response in Leukemia

“…Heterozygous, mutually exclusive missense mutations of IDH1/2 have been identified in AML [121], for example the R140G IDH2 mutant in myeloid cell lines [122]. TET2 mutations occur in around 50% of chronic myelomonocytic leukemia (CMML), a subtype of myelodysplastic syndrome/myeloid proliferative neoplasm (MDS/MPN) [124], as well as in around 30% of myeloproliferative neoplasms and AML [125]. Mutations in IDH1/2 and TET2 lead to a decrease in 5-hydroxymethylcytosine (5hmC) and consequently to DNA hypermethylation.…”

“…Mutations in IDH1/2 and TET2 lead to a decrease in 5-hydroxymethylcytosine (5hmC) and consequently to DNA hypermethylation. DNA hypermethylation is in part due to the inhibition of TET2 and the dioxygenases of the AlkB homolog (ALKBH) family, which are Fe (II) and α-ketoglutarate (α-KG)-dependent dioxygenases [126] that repair alkylated DNA [124,127]. When IDH1/2 are mutated, AKLBH enzymes lose their normal catalytic activity and gain activity, which leads to the reduction of α-KG into antagonistic D-2-hydroxyglutarate (D-2-HG), which in turn inhibits the AKLBH dioxygenases [126,128].…”