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• W2029002007 abstract "Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterized by the presence of different collaborating cytogenetic aberrations that are associated with outcome (Pui et al, 2011; Creutzig et al, 2012). New prognostically relevant genetic aberrations have recently been identified, such as mutations in NPM1 and FLT3, which further improve risk-group stratification, but the underlying genetic abnormalities are not fully understood in approximately 20% of paediatric AML cases (Pui et al, 2011; Creutzig et al, 2012). Unravelling the underlying aberrations involved in leukaemogenesis may improve risk-group stratification. PHF6 is an X-linked tumour suppressor gene, with a role in transcriptional regulation, and was identified as germline mutation causing Borjeson-Forssman-Lehmann syndrome (Liu et al, 2014; Meacham et al, 2015). PHF6 mutations are reported in adult T-acute lymphoblastic leukaemia (ALL), and somatic mutations in PHF6 were identified in 3% of adult AML, predominantly males, in cases with French-American-British (FAB) classifications M0, M1 and M2 (Van Vlierberghe et al, 2010, 2011; Patel et al, 2012). Whole genome sequencing identified PHF6 mutations in 2% of a paediatric AML series strongly enriched for core-binding factor AML (Huether et al, 2014). However, a large paediatric AML cohort has never been examined. In this study, we screened a large paediatric de novo AML cohort including all FAB-types, enriched for FAB-M0, M1 and M2, for PHF6 mutations. Samples were provided by the Dutch Childhood Oncology Group (DCOG, The Hague, The Netherlands), the AML–Berlin-Frankfurt-Münster Study Group (Germany and Czech Republic) and the Saint-Louis Hospital (France). Each study group provided centrally reviewed morphological and cytogenetic classification and clinical data, such as age at diagnosis, white blood cell count (WBC) and outcome. Institutional review board approval was obtained from the participating centres. Genomic DNA was amplified by polymerase chain reaction (PCR) and the purified products were directly sequenced and analysed using CLC Workbench (CLC Bio, Aarhus, Denmark, primers: Table S1). If an aberration was detected, RNA and germline or remission DNA was analysed, if available. Reverse transcription-PCR was performed on known hotspot areas and for the presence of fusion genes as previously described (de Rooij et al, 2013). A total of 318 de novo paediatric AML cases (175 males and 141 females; two patients unknown) were eligible for mutational screening, including 20 FAB-M0, 47 FAB-M1 and 76 FAB-M2 (Table 1). Direct sequencing analysis showed PHF6 mutations in 6/318 [2%; 95% confidence interval (95% CI): 0·9–4·1%] AML cases, representing 6/143 (4%; 95% CI: 1·9–8·9%) paediatric FAB M0, M1 and M2 cases. Most mutations were predicted to result in loss of function, with four truncating frameshift mutations and one point mutation in an intron resulting in loss of exon 4 at the RNA level (Fig S1A). In the latter case, germline material derived from fibroblasts did not harbour this aberration. Additionally, one missense variation (p.S145N, Fig S1B) was identified, which was also present in both complete remission and relapse samples, and predicted as damaging in SIFT and PolyPhen analysis. No single nucleotide polymorphisms are known at this position (http://www.ncbi.nlm.nih.gov/snp, http://www.ncbi.nlm.nih.gov/dbvar, accessed 17 February 2015); however, the variation is localized outside the most conserved PHD-finger domains. Based on the complete remission sample, this may be considered a germline variation. Median age at diagnosis was 12·6 years in the PHF6-mutated group, compared to 9·5 years in other paediatric AML (P = 0·11). Median WBC was 3·8 × 109/l and 43·0 × 109/l respectively (P = 0·03, Table 1). After successful induction, 4/6 mutated cases relapsed, and 1 patient did not experience an event. One other patient was a non-remitter. Two patients are alive in complete remission and four died from the disease. All PHF6-mutated cases were FAB subtype M0, M1 or M2. Other genetic abnormalities found in these cases were translocations RUNX1/RUNX1T1 and NUP98/KDM5A, and mutations in WT1, RAS, ETV6, TET2, IDH1 and BCORL1 (Table 2), none of which were recurrent in the PHF6-mutated group. Wang et al (2011) reported that PHF6 mutations were associated with the SET/NUP214 translocation in T-cell ALL. This translocation was present in 11 of our cases, but none harboured a PHF6 mutation. PHF6 mutations were almost exclusively found in males in reported series of T-ALL and adult AML (Van Vlierberghe et al, 2010, 2011). In our data, 4/6 of the patients with a mutation were female. Sex distribution did not differ significantly among the mutated cases (Fisher's exact test; P = 0·1), in contrast to the findings in adult AML (Van Vlierberghe et al, 2011). One female PHF6-mutated case showed loss of a sex chromosome in the leukaemic cells based on karyotyping. PHF6 is hypothesized to be inactivated on one copy of the X-chromosome in females due to lyonization. XIST mRNA expression was analysed by quantitative real-time PCR (qRT-PCR) using the average cycle threshold (Ct) in comparison to expression levels of GAPDH, using the comparative Ct method. XIST is highly expressed (>5% compared to GAPDH) if at least two X-chromosomes are present. The patient with known loss of an X-chromosome indeed showed low XIST expression (<1% compared to GAPDH). The other females with a PHF6 mutation showed high XIST expression, indicating both X-chromosomes were present in the leukaemic blasts. Whereas the frameshift mutations were heterozygous in female DNA, frameshift analysis at the RNA level showed mono-allelic presence of the mutated gene, indicating inactivation of the wild type PHF6 gene (Fig S1C). qRT-PCR analysis of PHF6 was performed on patients with available RNA (n = 240). PHF6 mRNA expression was similar in FAB-types M0, M1 and M2 to other FAB-types (Fig 1A). There was no difference in PHF6 expression between males and females (P = 0·7, Fig 1B). PHF6 expression was significantly lower in patients with a frameshift mutation compared to patients with normal predicted amino-acid length, suggesting the frameshifts result in a loss of function (P = 0·038, Fig 1C). When comparing mutated cases to patients with FAB-M0, M1 or M2 paediatric AML without PHF6 mutation, again a significant difference was found (P = 0·026, Fig 1D). Hairpin-mediated suppression of Phf6 promoted AML in vivo (Meacham et al, 2015). Accordingly, the presence of loss-of-function mutations in PHF6 in paediatric AML suggests a role for PHF6 in leukaemogenesis. Overall, our data show that PHF6 mutations occur at a low frequency in paediatric AML, exclusively in FAB-M0, M1 and M2, with significantly lower PHF6 mRNA expression. In contrast to T-ALL and adult AML, we found mutations of PHF6 in both female and male patients in paediatric AML. The potential prognostic impact of PHF6 mutations needs to be determined in a larger series. Jasmijn de Rooij was funded by Stichting Kinder Oncologisch Centrum Rotterdam (KOCR). Jasmijn de Rooij (JR), Marry van den Heuvel-Eibrink (MH), Nina van de Rijdt (NR) and Michel Zwaan (MZ) designed the study. MH, Valerie de Haas, Jan Trka, Andre Baruchel, Dirk Reinhardt, Rob Pieters (RP) and MZ provided patient samples, clinical characteristics and outcome data. JR, NR and Lonneke Verboon (LV) performed the research. MH, RP, Maarten Fornerod (MF) and MZ supervised the study. JR, NR, LV and MF analysed the data. JR, MH, NR, MF and MZ wrote the manuscript, and all authors critically reviewed the paper. The authors declare no conflict of interest Fig S1. PHF6 mutations in paediatric AML cases. Table S1. Primers used for mutational screening and qRT-PCR. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2029002007 title "<i>PHF6</i>mutations in paediatric acute myeloid leukaemia" @default.
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