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Acute myeloid leukemia

Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with acute myeloid leukemia


Previous studies demonstrated that splicing factor mutations are recurrent events in hematopoietic malignancies with both clinical and functional implications. However, their aberrant splicing patterns in acute myeloid leukemia remain largely unexplored. In this study, we characterized mutations in SRSF2, U2AF1, and SF3B1, the most commonly mutated splicing factors. In our clinical analysis of 2678 patients, splicing factor mutations showed inferior relapse-free and overall survival, however, these mutations did not represent independent prognostic markers. RNA-sequencing of 246 and independent validation in 177 patients revealed an isoform expression profile which is highly characteristic for each individual mutation, with several isoforms showing a strong dysregulation. By establishing a custom differential splice junction usage pipeline, we accurately detected aberrant splicing in splicing factor mutated samples. A large proportion of differentially used junctions were novel, including several junctions in leukemia-associated genes. In SRSF2(P95H) mutants, we further explored the possibility of a cascading effect through the dysregulation of the splicing pathway. Furthermore, we observed a validated impact on overall survival for two junctions overused in SRSF2(P95H) mutants. We conclude that splicing factor mutations do not represent independent prognostic markers. However, they do have genome-wide consequences on gene splicing leading to dysregulated isoform expression of several genes.

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Fig. 1: Frequency and location of SF mutations.
Fig. 2: Correlations between SF mutations and recurrent abnormalities.
Fig. 3: Multiple Cox regression models for overall survival.
Fig. 4: Differential isoform expression analysis in the AMLCG cohort.
Fig. 5: Differential splice junction usage.
Fig. 6: Splicing dysregulation in SRSF2 mutants.
Fig. 7: Impact of differential splice junction usage on overall survival.

Data availability

Read counts and sample characteristics are available in the GEO database (GSE146173). Law restrictions prohibit us from publicly sharing raw sequencing data, which however can be made available upon reasonable request and permission of the local ethics committee.


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The authors thank all participants and recruiting centers of the AMLCG, BEAT and AMLSG trials.


This work is supported by a grant of the Wilhelm-Sander-Stiftung (no. 2013.086.2) and the Physician Scientists Grant (G-509200–004) from the Helmholtz Zentrum München to T.H. and the German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung, Heidelberg, Germany). K.H.M., K.S., and T.H. are supported by a grant from Deutsche Forschungsgemeinschaft (DFG SFB 1243, TP A06 and TP A07). S.K.B. is supported by Leukaemia & Blood Cancer New Zealand and the family of Marijanna Kumerich. A.M.N.B. is supported by the BMBF grant 01ZZ1804B (DIFUTURE).

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S.A.B., A.M.N.B., and T.H. conceived and designed the analysis. S.A.B., A.M.N.B., V.J., M.R.-T., H.J., A.G., S.C., N.K., K.S., K.H.M., and T.H. provided and analyzed data. A.M.N.B., V.J., and U.M. provided bioinformatics support. J.P.-M., S.K., and H.B. managed the HiSeq 1500 instrument and the RNA-sequencing of the AMLCG samples. M.R.-T., H.J., B.K., S.S., N.K., S.K.B., K.H.M., and K.S. characterized patient samples; M.C.S., D.G., W.B., B.W., J.B., and W.H. coordinated the AMLCG clinical trials. S.A.B. and T.H. wrote the manuscript. All authors approved the final manuscript.

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Correspondence to Stefanos A. Bamopoulos or Tobias Herold.

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H.J. is a current employee of Roche Pharma AG, Grenzach-Wyhlen, Germany. The authors declare that they have no conflict of interest.

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Bamopoulos, S.A., Batcha, A.M.N., Jurinovic, V. et al. Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with acute myeloid leukemia. Leukemia 34, 2621–2634 (2020).

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