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Chronic Lymphocytic Leukemia

SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients

Leukemia volume 28, pages 108–117 (2014)Cite this article

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Abstract

We analyzed a large cohort of 1160 untreated CLL patients for novel genetic markers (SF3B1, NOTCH1, FBXW7, MYD88, XPO1) in the context of molecular, immunophenotypic and cytogenetic data. NOTCH1 mutations (mut) (12.3%), SF3B1mut (9.0%) and TP53mut (7.1%) were more frequent than XPO1mut (3.4%), FBXW7mut (2.5%) and MYD88mut (1.5%). SF3B1mut, NOTCH1mut, TP53mut and XPO1mut were highly correlated to unmutated, whereas MYD88mut were associated with mutated IGHV status. Associations of diverse cytogenetic aberrations and mutations emerged: (1) SF3B1mut with del(11q), (2) NOTCH1mut and FBXW7mut with trisomy 12 and nearly exclusiveness of SF3B1mut, (3) MYD88mut with del(13q) sole and low frequencies of SF3B1mut, NOTCH1mut and FBXW7mut. In patients with normal karyotype only SF3B1mut were frequent, whereas NOTCH1mut rarely occurred. An adverse prognostic impact on time to treatment (TTT) and overall survival (OS) was observed for SF3B1mut, NOTCH1mut and TP53 disruption. In multivariate analyses SF3B1mut, IGHV mutational status and del(11q) were the only independent genetic markers for TTT, whereas for OS SF3B1mut, IGHV mutational status and TP53 disruption presented with significant impact. Finally, our data suggest that analysis of gene mutations refines the risk stratification of cytogenetic prognostic subgroups and confirms data of a recently proposed model integrating molecular and cytogenetic data.

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Acknowledgements

We thank all co-workers in our laboratory for their excellent technical assistance and all patients and clinicians for their participation in this study. Next-generation deep-sequencing studies were supported in part by the IRON-II study framework (Roche Diagnostics, Penzberg, Germany).

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  1. MLL Munich Leukemia Laboratory, Munich, Germany

    S Jeromin, S Weissmann, C Haferlach, F Dicker, K Bayer, V Grossmann, T Alpermann, A Roller, A Kohlmann, T Haferlach, W Kern & S Schnittger

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  1. S Jeromin
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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. SJ, SW, VG, KB, FD, TA, AR and AK are employed by the MLL Munich Leukemia Laboratory.

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SJ and SS designed the study, interpreted the data and wrote the manuscript. SJ, SW, VG, KB, FD and AK did molecular analyses. CH was responsible for chromosome banding and FISH analyses, WK for immunophenotyping and TH for cytomorphologic analyses. AR and TA collected and analyzed clinical data. All authors read and contributed to the final version of the manuscript.

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Jeromin, S., Weissmann, S., Haferlach, C. et al. SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients. Leukemia 28, 108–117 (2014). https://doi.org/10.1038/leu.2013.263

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