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

Ly, S.; Dc, Liang; Huang, Chongmei; Yt, Chang; Lai, CL; Ts, Lin; Cp, Yang; Ij, Hung; Hc, Liu; Th, Jaing; Ly, Wang; Tc, Yeh

doi:10.1038/sj.leu.2404995

Cited by 69 publications

(71 citation statements)

References 35 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%

“…Immunophenotyping and cytogenetic/ genetic analyses were performed at initial diagnosis as has been described previously. 23,24 MLL gene rearrangement was screened by cytogenetics, Southern blot analysis, or fluorescent in situ hybridization followed by reverse transcriptase-polymerase chain reaction (PCR) assays or panhandle PCR to detect the MLL fusion transcripts as previously described. 25 The earlier cohort of patients with acute promyelocytic leukemia (APL) was treated with the Taiwan Pediatric Oncology Group (TPOG)-APL-97 protocol, which consisted of all-trans retinoic acid followed by idarubicin and cytarabine.…”

Section: Patients and Samplesmentioning

confidence: 99%

“…19 DNMT3A mutations have been rare in pediatric patients with AML: in one study that included 180 cases, no patients were found, 20 and only 1.0% and 2.1% of the patients in the other two studies were reported. 21,22 In this study of 206 pediatric patients with de novo AML, we systematically analyzed known mutated genes, examined more patients and genes than we have reported previously, 23 and included 5 recently identified genes that encode epigenetic modifiers. We also The online version of this article contains a data supplement.…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Patients and Samplesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Retrospective studies have demonstrated that the presence of KIT mutations in exon 17 have been associated with a poor outcome in CBF-AML and, for that reason, KIT mutation testing has been recently incorporated into National Cancer Guidelines to better stratify such patients in different prognostic subgroups [25]. However, while several studies showed that activating KIT mutations confer a significantly lower survival in AML with t(8;21)(q22;q22), the negative prognostic impact of KIT mutations in CBFb-AML remains controversial [24,[26][27][28][29][30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Old and new prognostic factors in acute myeloid leukemia with deranged core‐binding factor beta

et al. 2013

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Acute myeloid leukemia (AML) with deranged core‐binding factor beta (CBFβ) is usually associated with a favorable prognosis with 50–70% of patients cured using contemporary treatments. We analyzed the prognostic significance of clinical features on 58 patients with CBFβ‐AML aged ≤60 years. Increasing age was the only predictor for survival (P <0.001), with an optimal cut‐point at 43 years. White blood cells (WBCs) at diagnosis emerged as an independent risk factor for relapse incidence (P = 0.017), with 1.1% increase of hazard for each 1.0 × 109/L WBC increment. KIT mutations lacked prognostic value for survival and showed only a trend for relapse incidence (P = 0.069). Am. J. Hematol. 88:594–600, 2013. © 2013 Wiley Periodicals, Inc.

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“…Although it is likely that an unidentified Class II mutation may exist, this "exception" has been observed in other studies. [16][17] A model utilizing information from the Cancer Genome Atlas recently predicted that NRAS activating mutations would coexist with KIT mutations in hematopoietic malignancies and were, therefore, strong candidates for cosequencing.…”

mentioning

confidence: 99%

Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis

Wilson¹,

Marić²,

Šimáková³

et al. 2010

Haematologica

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Cooperating genetic events are likely to contribute to the phenotypic diversity of KIT-D816V systemic mastocytosis. In this study, 44 patients with KIT-D816V systemic mastocytosis were evaluated for coexisting NRAS, KRAS, HRAS or MRAS mutations. Activating NRAS mutations were identified in 2 of 8 patients with advanced disease. NRAS mutations were not found in patients with indolent systemic mastocytosis. To better understand the clonal evolution of mastocytosis, we evaluated the cell compartments impacted by the NRAS and KIT mutations. Clonal mast cells harbored both mutations. KIT-D816V was not detected in bone marrow CD34 + progenitors, whereas the NRAS mutation was present. These findings suggest that NRAS mutations may have the potential to precede KIT-D816V in clonal development. Unlike other mature lineages, mast cell survival is dependent on KIT and the presence of these two activating mutations may have a greater impact on the expansion of this cell compartment and in resultant disease severity. (Clinicaltrials.gov identifier: NCT00044122, NCT00001756)

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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

Cited by 69 publications

References 35 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

Old and new prognostic factors in acute myeloid leukemia with deranged core‐binding factor beta

Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis

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