TET2 mutations in childhood leukemia

Langemeijer, Saskia; Jansen, Joop H.; Hooijer, Jeroen D; Hoogen, P.C.M. van; Stevens-Linders, Ellen; Massop, Marion; Waanders, Esmé; Reijmersdal, S.V. van; Stevens‐Kroef, Marian; Zwaan, C. Michel; Heuvel‐Eibrink, Marry M. van den; Sonneveld, Edwin; Hoogerbrugge, Peter M.; Kessel, A.H.M. Geurts van; Kuiper, Roland P.

doi:10.1038/leu.2010.243

Cited by 51 publications

(34 citation statements)

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“…[57][58] Interestingly, in agreement with the hypothesis that AML results from a multistep pathogenesis, these aberrations might add an additional class of mutations as aberrant TET2, IDH1 and -2 and DNMT3A have been shown to affect the epigenetic landscape of AML. Recent studies, however, indicated that these mutations might be rare in pediatric AML, [59][60][61] stressing the need for separate pediatric studies to discover the remaining genetic aberrations, including aberrations in miRNA-coding genes or in methylation of genes or their promoter regions.…”

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Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia

Balgobind¹,

Hollink²,

et al. 2011

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The online version of this article has a Supplementary Appendix. BackgroundSeveral studies of pediatric acute myeloid leukemia have described the various type-I or type-II aberrations and their relationship with clinical outcome. However, there has been no recent comprehensive overview of these genetic aberrations in one large pediatric acute myeloid leukemia cohort. Design and MethodsWe studied the different genetic aberrations, their associations and their impact on prognosis in a large pediatric acute myeloid leukemia series (n=506). Karyotypes were studied, and hotspot regions of NPM1, CEPBA, MLL, WT1, FLT3, N-RAS, K-RAS, PTPN11 and KIT were screened for mutations of available samples. The mutational status of all type-I and type-II aberrations was available in 330 and 263 cases, respectively. Survival analysis was performed in a subset (n=385) treated on consecutive acute myeloid leukemia Berlin-Frankfurt-Munster Study Group and Dutch Childhood Oncology Group treatment protocols. ResultsGenetic aberrations were associated with specific clinical characteristics, e.g. significantly higher diagnostic white blood cell counts in MLL-rearranged, WT1-mutated and FLT3-ITD-positive acute myeloid leukemia. Furthermore, there was a significant difference in the distribution of these aberrations between children below and above the age of two years. Non-random associations, e.g. KIT mutations with core-binding factor acute myeloid leukemia, and FLT3-ITD with t(15;17)(q22;q21), NPM1-and WT1-mutated acute myeloid leukemia, respectively, were observed. Multivariate analysis revealed a 'favorable karyotype', i.e. t(15;17)(q22;q21), t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22). NPM1 and CEBPA double mutations were independent factors for favorable event-free survival. WT1 mutations combined with FLT3-ITD showed the worst outcome for 5-year overall survival (22±14%) and 5-year eventfree survival (20±13%), although it was not an independent factor in multivariate analysis. ConclusionsIntegrative analysis of type-I and type-II aberrations provides an insight into the frequencies, non-random associations and prognostic impact of the various aberrations, reflecting the heterogeneity of pediatric acute myeloid leukemia. These aberrations are likely to guide the stratification of pediatric acute myeloid leukemia and may direct the development of targeted therapies.

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confidence: 99%

Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia

Balgobind¹,

Hollink²,

et al. 2011

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“…11,13,19,22,39 As TET2 mutations were first described to be involved in myeloid malignancies, 11,12 data of polymorphisms in TET2 are constantly growing. 22,35,40 For example, Metzeler et al 22 recently published that all of the seven investigated missense mutations located outside the conserved domains were germline variants. However, these data are generally controversial as Abdel-Wahab et al…”

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Landscape of TET2 mutations in acute myeloid leukemia

et al. 2011

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We investigated ten --eleven translocation 2 (TET2) mutations in acute myeloid leukemia (AML), their correlation with other gene mutations and prognostic value. By deep-sequencing, 131 somatic TET2 mutations were identified in 87/318 (27.4%) patients. Of 87 mutated cases, 44 (50.6%) carried two mutations. TET2 mutations were concomitantly observed with mutations in NPM1, FLT3-ITD, FLT3-TKD, JAK2, RUNX1, CEBPA, CBL and KRAS. However, TET2 mutations rarely concomitantly occurred with IDH1mut or IDH2mut (2/251 or 0/184; P ¼ 0.046 and P ¼ 0.003, respectively). TET2 mutations were associated with normal karyotype AML (CN-AML) (62/206 (30.1%) CN-AML vs 20/107 (18.7%) aberrant karyotype; P ¼ 0.031), higher white blood cell count (mean 65.3 vs 40.3 Â 10 9 /l, P ¼ 0.023), lower platelet count (mean 68.6 vs 92.4 Â 10 9 /l, P ¼ 0.03) and higher age (67.5 vs 65.2 years, Po0.001). Survival analyses were restricted to de novo CN-AML patients (n ¼ 165) and showed inferior event-free survival (EFS) of TET2 mutations compared with TET2wt (median: 6.7 vs 18.7 months, P ¼ 0.009). This negative effect of TET2 mutation on EFS was particularly observed in patients p65 years (median: 8.9 months vs not reached (n.r.), P ¼ 0.027) as well as in patients of the European LeukemiaNet favorable-risk subgroup, that is, patients harboring mutated CEBPA and/or mutated NPM1 without FLT3-ITD (median: 10.3 vs 41.3 months, P ¼ 0.048). These data support a role for TET2 as an important prognostic biomarker in AML.

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“…Исследования однонуклеотидных полиморфизмов при ОМЛ с помощью сравнительной геномной ги-бридизации выявили рекуррентные аберрации, такие как WT1, NF1, TET2, что еще больше усложнило по-иск таргетных точек в терапии ОМЛ [19]. Тем не менее новые гены, такие как BRE и IGSF4, были выявлены именно методом исследования генной экспрессии [14].…”

Section: новообразование из бластных плазмоцитоидных дендритных клетокunclassified

Acute myeloid leukemia in children. Prospects for the optimization of treatment (review)

Румянцев¹

2017

Ross. ž. det. gematol. onkol.

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TET2 mutations in childhood leukemia

Cited by 51 publications

References 9 publications

Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia

Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia

Landscape of TET2 mutations in acute myeloid leukemia

Acute myeloid leukemia in children. Prospects for the optimization of treatment (review)

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