Cooperating gene mutations in childhood acute myeloid leukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2, and DNMT3A

Abstract

Key Points• A comprehensive study of 19 gene mutations and their cooperation, including the first report of ASXL1 and TET2 mutations in pediatric AML.• The development of pediatric AML requires fewer gene mutations than adult AML.Gene mutations involving epigenetic regulators recently have been described in adult acute myeloid leukemia (AML). Similar studies are limited in children. We analyzed gene mutations and cooperation in pediatric AML with special reference on mutated epigenetic regulators. Nineteen gene mutations, including 8 class I genes, 4 class II genes, WT1 and TP53 (class III), and 5 epigenetic regulator genes (class IV), were analyzed in 206 children with de novo AML. Mutational analysis was performed with polymerase chain reaction2 based assay followed by direct sequencing. One hundred seventeen of 206 patients (56.8%) had at least one mutation: 51% class I, 13% class II, 6.8% class III, and 5.6% class IV. FLT3-internal tandem duplication was most frequent, and 29% of patients had more than one gene mutation. Two patients carried ASXL1 mutations, both with t(8;21), 2 had DNMT3A mutations, 2 had IDH1 mutations, 1 had IDH2 mutation, and 3 had TET2 mutations. Both patients with IDH1 mutations had AML-M0 subtype and MLL-partial tandem duplication. Cooperating mutations with mutated epigenetic regulators were observed in 8 of 10 patients. We conclude that mutated epigenetic regulators were much less than those in adult AML but with frequent cooperating mutations. ASXL1, TET2, and IDH1 mutations were associated with specific genetic subtypes. (Blood. 2013;121(15):2988-2995 IntroductionComprehensive analyses in de novo childhood acute myeloid leukemia (AML) of gene mutations involving epigenetic regulators have been limited. The ASXL1 (additional sex comb-like 1) gene mapping to chromosome 20q acts as a cofactor of retinoic acid receptor via binding to steroid receptor coactivation-1 and belongs to enhancer of trithorax and polycomb genes that can both activate and repress the HOX gene.1,2 Very recently, it has been demonstrated that ASXL1 loss-of-function mutations result in the loss of polycomb repressive complex 22mediated histone H3 lysine 27 trimethylation, which promotes myeloid leukemia transformation.3 ASXL1 mutations conferred a poor outcome in adult AML, 4,5 but there have been no reports of ASXL1 mutations in childhood AML. TET proteins encode a-ketoglutarate-dependent oxygenases, which are involved in the conversion of 5-methylcytosine to 5-hydroxymethylcytosine. 6 TET2 protein is important for normal myelopoiesis, and disruption of TET2 enzymatic activity results in altered DNA methylation and favors myeloid neoplasm transformation.7 IDH1 and IDH2 mutations convert a-ketoglutarate to 2-hydroxyglutarate, which disrupts TET2 function. 8,9 Somatic mutations of TET2 were identified with microdeletion at 4q24 in myeloid neoplasms by the use of high-resolution single-nucleotide polymorphism microarrays.10,11 TET2 mutations were detected in adult AML with a frequency ranging from 7% to 23%, but t...

Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation

“…9,[18][19][20]24,25 In general, ASXL1 mutations are also rare in pediatric AML. 26,27 However, this was not seen in GATA2 deficiency patients. The average age of GATA2 deficiency patients with an ASXL1 mutation (35.8 ± 12.8 years old, range, 17-59 years old) was markedly younger than that of other MDS/AML groups, but not significantly different from that of GATA2 deficiency patients without an ASXL1 mutation (34.5±17.0 years old, range 10-78 years old) (ttest, P=0.81) ( Figure 2B).…”

Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations

“…19 The mutational status of IDH1/2 in 71 of the 168 patients had been reported before. 13 TET2/IDH mutated cases were measured both at diagnosis of MDS and on progression to sAML by pyrosequencing and/or deep sequencing of the relevant mutant alleles.…”

The de novo DNA methyltransferase DNMT3A in development and cancer

“…89 Although previous studies clearly pointed to an oncogenic role of DNMT3A in cancer, the recent discovery of genetic mutations of DNMT3A in acute myeloid leukemia (AML) suggested that its role in cancers may be more complex than was previously believed. [11][12][13][14][15][16][17][18][19][20][21][22][23] These highly recurrent DNMT3A mutations were closely associated with poor outcome in patients with AML. However, the functional implications of these mutations are still poorly understood.…”

“…10 However, several inactivating mutations of DNMT3A in myeloid malignancies [11][12][13][14][15][16][17][18][19][20][21][22][23] and loss of DNMT3A activity at advanced tumor stages 24 were recently identified. In addition, novel roles of DNMT3A in the hematopoiesis system 25 and in the age-related decline of cognition 26 have been revealed.…”