DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies

Abstract

The development of effective treatment strategies for most forms of acute myeloid leukemia (AML) has languished for the past several decades. There are a number of reasons for this, but key among them is the considerable heterogeneity of this disease and the paucity of molecular markers that can be used to predict clinical outcomes and responsiveness to different therapies. The recent large-scale sequencing of AML genomes is now providing opportunities for patient stratification and personalized approaches to treatment that are based on individual mutational profiles. It is particularly notable that studies by The Cancer Genome Atlas and others have determined that 44% of patients with AML exhibit mutations in genes that regulate methylation of genomic DNA. In particular, frequent mutation has been observed in the genes encoding DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2), as well as Tet oncogene family member 2. This review will summarize the incidence of these mutations, their impact on biochemical functions including epigenetic modification of genomic DNA and their potential usefulness as prognostic indicators. Importantly, the presence of DNMT3A, IDH1 or IDH2 mutations may confer sensitivity to novel therapeutic approaches, including the use of demethylating agents. Therefore, the clinical experience with decitabine and azacitidine in the treatment of patients harboring these mutations will be reviewed. Overall, we propose that understanding the role of these mutations in AML biology will lead to more rational therapeutic approaches targeting molecularly defined subtypes of the disease.

Absence of DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 hotspot mutations in patients with various subtypes of ovarian carcinomas

“…Some of these mutations were closely associated with cancer progression (22) and prognosis (23,24). Thus far, the mutation statuses of DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 mutational hotspots in ovarian carcinomas remain largely unknown.…”

Sequence variations of mitochondrial DNA D‑loop region in patients with acute myeloid leukemia

“…However, the aforementioned gene alterations alone have not fully elucidated the pathogenesis of AML, thus, current studies have focused on identifying novel biomarkers. The majority of studies have focused on the nuclear genome (2)(3)(4)(5), with less focus on the extranuclear genome (mitochondrial genome).…”

“…Clonal chromosome alterations and fusion genes were firstly recognized, and were regarded as the most potent biomarkers for AML therapeutic response and survival prognosis (1). Subsequently, several gene mutations, including FLT3-internal tandem duplication, FLT3-tyrosine kinase domain, DNA methyltransferase 3α, isocitrate dehydrogenase and CCAAT/enhancer binding protein α mutations, have been identified to participate in the abnormal proliferation of leukemia progenitor cells or impaired differentiation (2)(3)(4). In addition, they have been identified as valuable prognostic biomarkers that affect the therapeutic regimen decision (2)(3)(4).…”

“…Subsequently, several gene mutations, including FLT3-internal tandem duplication, FLT3-tyrosine kinase domain, DNA methyltransferase 3α, isocitrate dehydrogenase and CCAAT/enhancer binding protein α mutations, have been identified to participate in the abnormal proliferation of leukemia progenitor cells or impaired differentiation (2)(3)(4). In addition, they have been identified as valuable prognostic biomarkers that affect the therapeutic regimen decision (2)(3)(4). However, the aforementioned gene alterations alone have not fully elucidated the pathogenesis of AML, thus, current studies have focused on identifying novel biomarkers.…”

Genomic profiling and directed ex vivo drug analysis of an unclassifiable myelodysplastic/myeloproliferative neoplasm progressing into acute myeloid leukemia

“…Similar to the ara-C resistant cell line THP-1 (Ge et al, 2004), the AML cells had relatively high IC50 for this drug. Finally, decitabine is approved for treatment of high-risk MDS (Im et al, 2014) and may improve the complete remission rates in AML (Metzeler et al, 2012) and MDS patients (Traina et al, 2014) with DNMT3A mutations.…”