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Acute Leukemias

ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome

Abstract

We aimed at evaluating ASXL1mut in 740 AML with intermediate risk karyotype for frequency, association with other mutations and impact on outcome. Five hundred fifty-three cases had a normal karyotype (NK) and 187 had intermediate risk aberrant cytogenetics. Overall, ASXL1mut were detected in 127/740 patients (17.2%). ASXL1mut were more frequent in males than in females (23.5% vs 9.9%, P<0.001). They were associated with higher age (median: 71.8 vs 61.8, P<0.001), a history of preceding myelodysplastic syndromes, and with a more immature immunophenotype compared with patients with wild-type ASXL1 (ASXL1wt). ASXL1mut were more frequent in patients with aberrant karyotype (58/187; 31.0%), especially in cases with trisomy 8 (39/74; 52.7%), than in those with NK (69/553; 12.5%; P<0.001). ASXL1mut were observed more frequent in RUNX1mut (P<0.001), and less frequent in NPM1mut (P<0.001), FLT3-internal tandem duplication (ITD) (P<0.001), FLT3-TKD (P=0.001) and DNMT3Amut (P<0.001). Patients with ASXL1mut had a shorter overall survival (OS) (P<0.001) and event free survival (P=0.012) compared with ASXL1wt. In multivariable analysis, ASXL1mut was an independent adverse factor for OS (P=0.032, relative risk: 1.70). In conclusion, ASXL1mut belong to the most frequent mutations in intermediate risk group AML. Their strong and independent dismal prognostic impact suggests the inclusion into the diagnostic work-up of AML.

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Acknowledgements

We thank all coworkers in our laboratory for their excellent technical assistance. We also thank Hubert Serve, Johann Wolfgang Goethe-University, Frankfurt; Dietrich Braumann, Asklepios Klinik Altona, Hamburg; Hermann-Josef Pielken, St Johannes Hospital, Dortmund; Clemens-Martin Wendtner, Klinikum Schwabing, Munich; Tanja Hesse, Klinikum Lippe, Lemgo; Hans-Jörg Weh, Franziskus Hospital, Bielefeld; Jürgen Wehmeyer, Gemeinschaftspraxis für Hämatologie und Onkologie, Münster; Heinz-Gert Höffkes, Klinikum Fulda; Michael Flasshove, Krankenhaus Düren, Düren; Michael Rummel, Justus Liebig University, Gießen; Christian Peschel, Klinikum Rechts der Isar der Technischen Universität München, Munich; Andreas Neubauer, Philipps University, Marburg and all other physicians for referring samples to our center.

Author contributions

SS was the principal investigator of this study, analyzed the data and wrote the paper. CE and AF did sequence analysis of ASXL1. AK and VG performed next-generation sequencing. SJ contributed to writing of the paper. KAK, CS, PS, RP, and NS provided patient samples and clinical data. CH was responsible for chromosome banding analysis. WK was responsible for immunophenotyping and was involved in the statistical analysis. TH was responsible for cytomorphologic analysis. TA collected and analyzed clinical data. All authors read and contributed to the final version of the paper.

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Correspondence to S Schnittger.

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SS, WK, CH, and TH are part owners of the MLL Munich Leukemia Laboratory. CE, SJ, TA, AF, VG and AK are employed by the MLL Munich Leukemia Laboratory.

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Schnittger, S., Eder, C., Jeromin, S. et al. ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia 27, 82–91 (2013). https://doi.org/10.1038/leu.2012.262

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