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

Abstract

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.

Pediatric Acute Myeloid Leukemia

“…(Brown, et al 2007, Ho, et al 2009, Hollink, et al 2011, Hollink, et al 2009c In addition, the following type-1 mutations were identified: FLT3-internal tandem duplications (FLT3-ITD), found in ~30-40% of cases, FLT3-tyrosine kinase domain mutations (FLT3-TKD) in ~2% and N-or K-RAS mutations in ~15-20% of CN-AML cases. (Balgobind, et al 2011a, Goemans, et al 2005 WT1 mutations were found in 20-25% of pediatric CN-AML cases, in approximately half of the cases together with a FLT3-ITD, and in a quarter together with a RAS-mutation. (Balgobind, et al 2011a, Ho, et al 2010b, Hollink, et al 2009a In 20-25% of cases no type-I aberration can be detected so far.…”

“…Some of these mutations cluster in cytogenetically-normal AML, which is found in 20-25% of pediatric AML cases, which is a lower frequency than in adults, where approximately 50% of cases do not have cytogenetic abnormalities. (Balgobind, et al 2011a, Marcucci, et al 2011 NPM1 and CEBPA gene mutations confer good clinical outcome, whereas mutations in the FLT3 and WT1-genes confer poor clinical outcome. (Ho, et al 2009, Ho, et al 2010b, Hollink, et al 2011, Hollink, et al 2009a, Hollink, et al 2009c, Zwaan, et al 2003a Figure 2 shows the distribution of type 1 and 2 abnormalities, as identified in >400 cases of pediatric AML.…”

“…(Balgobind, et al 2011a, Harrison, et al 2010 Over the past few years many gene mutations or overexpression of specific genes have been identified in CN-AML, with clear prognostic impact. (Hollink, et al 2009b) This includes typical type II aberrations such as NPM1 mutations in ~20%, CEPBA double mutations in ~15-20% of cases.…”

“…(Hollink, et al 2009b) This includes typical type II aberrations such as NPM1 mutations in ~20%, CEPBA double mutations in ~15-20% of cases. (Balgobind, et al 2011a) The NPM1 and CEBPA double mutations confer good clinical outcome, allowing risk-stratification with the "good risk" cytogenetic subgroups. (Brown, et al 2007, Ho, et al 2009, Hollink, et al 2011, Hollink, et al 2009c In addition, the following type-1 mutations were identified: FLT3-internal tandem duplications (FLT3-ITD), found in ~30-40% of cases, FLT3-tyrosine kinase domain mutations (FLT3-TKD) in ~2% and N-or K-RAS mutations in ~15-20% of CN-AML cases.…”

Low frequency of type-I and type-II aberrations in myeloid leukemia of Down syndrome, underscoring the unique entity of this disease

“…internal tandem duplications, ITD) and tyrosine kinase domain mutations (TKD), N-RAS and K-RAS, PTPN11, KIT, IDH1/ IDH2, and the DNMT3A genes, as previously described. 1,5 In addition, we investigated the presence of the cryptic translocation NUP98/NSD1 by reverse transcriptase-polymerase chain reaction (RT-PCR).…”