FLT3-TKD mutation in childhood acute myeloid leukemia

Dc, Liang; Ly, S.; Ij, Hung; Cp, Yang; Sh, Chen; Th, Jaing; Hc, Liu; Ly, Wang; Chang, Wen Ho

doi:10.1038/sj.leu.2402928

Cited by 64 publications

(67 citation statements)

References 33 publications

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“…Detections of gene mutations, including FLT3-internal tandem duplication (ITD), FLT3-tyrosine kinase domain (TKD), C-FMS (exons 6-22), C-KIT (exons 7-21), exons 2 and 3 of NRAS and KRAS, MLL-partial tandem duplication (PTD), and the entire coding sequences of CEBPa and RUNX1 were performed as previously described, 23,25,[29][30][31] and the results were updated in the present study.…”

Section: Mutational Analysismentioning

confidence: 99%

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

Liang

Liu

Yang

et al. 2013

Blood

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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...

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Section: Mutational Analysismentioning

confidence: 99%

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

Liang

Liu

Yang

et al. 2013

Blood

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“…22 The detection of FLT3-TKD mutations was performed as described previously. 24 DNA PCR or RT-PCR followed by direct sequencing was performed to detect mutations at codons 12, 13 and 61 of the N-and K-Ras genes. 25 …”

Section: Detection Of Csf1r Mutationsmentioning

confidence: 99%

Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples

Huang

et al. 2007

Leukemia

Self Cite

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“…The clinical impact of differentiating, immune or targeted therapies [25][26][27][28][29] could be assessed at the best once minimal residual disease has been achieved, after consolidation therapy.…”

Section: Maintenance Therapymentioning

confidence: 99%

Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit – multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group

Pérel¹,

Auvrignon²,

Leblanc³

et al. 2005

Leukemia

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From 1989 to 1998, 341 children were included in the French multicentric LAME (Leucé mie Aiguë Myé loblastique Enfant) trials. A total of 309 children were registered in the LAME 89/91 protocol. This intensive regimen included an induction phase (mitoxantrone plus cytarabine), two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase and amsacrine; 276 (90%) achieved a CR. The 5-year overall survival (OS) and event-free survival (EFS) were 6074 and 4874%, respectively. From 1997, timed-sequencing of the LAME SP induction chemotherapy led to an unacceptable frequency of consolidation delay; future improvements are unlikely to come from further increases in intensity. The role of allogenic bone-marrow transplantation from an HLA-identical sibling in CR1 was examined. The disease-free survival (DFS) was 5274% for non-allografted patients and 5777% for allografted patients (P ¼ NS); a better OS for allografted patients was shown and could be related either to allo-BMT early in CR1 or to a second allo-BMT in CR2. For the complete responders after consolidation therapy, the 5-year OS was significantly better in patients randomized for no maintenance therapy (MTÀ) than in patients randomized for MT (77.678 vs 5978%; P ¼ 0.05), while the 5-year DFS was not significantly different. Exposure to low-dose MT might contribute to clinical drug resistance and treatment failure in relapsing patients.

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FLT3-TKD mutation in childhood acute myeloid leukemia

Cited by 64 publications

References 33 publications

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

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

Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples

Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit – multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group

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