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. 2011 Oct;96(10):1478-87.
doi: 10.3324/haematol.2010.038976. Epub 2011 Jul 26.

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

Brian V Balgobind  1 , Iris H I M Hollink, Susan T C J M Arentsen-Peters, Martin Zimmermann, Jochen Harbott, H Berna Beverloo, Anne R M von Bergh, Jacqueline Cloos, Gertjan J L Kaspers, Valerie de Haas, Zuzana Zemanova, Jan Stary, Jean-Michel Cayuela, Andre Baruchel, Ursula Creutzig, Dirk Reinhardt, Rob Pieters, C Michel Zwaan, Marry M van den Heuvel-Eibrink
Affiliations

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

Brian V Balgobind et al. Haematologica. 2011 Oct.

Abstract

Background: Several 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 methods: We 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.

Results: Genetic 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 event-free survival (20±13%), although it was not an independent factor in multivariate analysis.

Conclusions: Integrative 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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Figures

Figure 1.
Figure 1.
Distribution of the different type-I and type-II aberrations in pediatric AML. The heterogeneity of pediatric AML is reflected by the presence of the different type-I and type-II genetic aberrations. However, in a large number of cases the type-II (A) or type-I (B) aberrations have not yet been identified.
Figure 2.
Figure 2.
Type-I aberrations per type-II defined subtype. Distribution of the different type-I aberrations according to the different type-II defined subtypes including more than 10 cases, i.e. MLL-rearrangements, t(8;21), inv(16), t(15;17), NPM1-mutated and CEBPA double mutated AML.
Figure 3.
Figure 3.
Survival analysis of the type-I and type-II aberrations in pediatric AML. Kaplan-Meier estimates for (A+D) pOS, (B+E) pEFS and (C+F) CIR for the different type-II and type-I aberrations, respectively.
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