The Epigenetic Landscape of Acute Myeloid Leukemia

Table 1

Key genetic mutations thought to have implications for prognosis in AML. The genetic mutations included in the table are reviewed below. Table compiled with information from [29, 32, 35, 39, 50, 52, 58, 61, 66, 67, 73, 76, 80, 86–96].

Gene	Mutation type	Mutation frequency	Consequence of mutation	Prognostic implications	Initiating lesion
DNMT3A	Mainly missense; 60% at R882; Often heterozygous	15–25% AML	R882 mutations reduce binding affinity and catalytic activity—LOF	Likely poorer prognosis. Affected by R882/non-R882, CM, patient age Adverse prognosis in intermediate risk AML	Uncertain
TET2	46% frame shift; Also missense, nonsense, and splice site variations; Majority heterozygous	7–23% AML; 10–20% MPN/MDS	Truncated protein and consequent reduction in hydroxymethylation—LOF∗	Poorer prognosis in favorable risk CN-AML; No effect in MPN, possibly improved prognosis in MDS	Early event, possibly initiating
IDH1 + 2	Amino acid substitutions; R132 (IDH1); R172, and R140 (IDH2); Heterozygous	15–30% AML; 5% MPN/MDS	Neomorphic gain of function; Production of 2-HG, inhibition of TET2 function	Unclear—R140Q may have favorable effect on prognosis R132H/R172K may have no effect; However some studies suggest IDH mutations have adverse impact on favorable CN-AML NPM1^mut/IDH^mut AML has a favorable outcome	Early event, possibly initiating
ASXL1	Nonsense, missense, frame shift, and point mutations	10–15% MPN/AML; 10–25% MDS	Uncertain if function lost or gained—research suggests reduced ASXL1 expression	Poor prognostic marker in AML and MPN	Very early, increased leukemic progression in MPN
EZH2	Missense, nonsense, and frame shift	Occasional in AML; MDS 7%; MPN 3–13%	Truncated SET domain—LOF; Gain of function observed in other malignancies	Worse OS in MDS, CMML, and PMF; (del)7q poor prognostic indicator in MDS—probably in part due to loss of EZH2	Very early event in MPN, probably not leukemic initiator

∗LOF: loss of function.