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Activating CBL mutations are associated with a distinct MDS/MPN phenotype

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Abstract

Activating point mutations in CBL have recently been identified in diverse subtypes of myeloid neoplasms. Because detailed clinical and hematological characteristics of CBL-mutated cases is lacking, we screened 156 BCR-ABL and JAK2 V617F negative patients with myeloproliferative neoplasms (MPN) and overlap syndromes between myelodysplastic syndrome (MDS) and MPN (MPS/MPN) for mutations in exons 8 and 9 of CBL by denaturing high-performance liquid chromatography and direct sequencing. CBL mutations were identified in 16/156 patients (10 %), of which five also carried mutations in EZH2 (n = 3) and TET2 (n = 2). Comprehensive clinical and hematological characteristics were available from 13/16 patients (81 %). In addition to splenomegaly (77 %), striking common hematological features were CML-like left-shifted leukocytosis (85 %) with monocytosis (85 %), anemia (100 %), and thrombocytopenia (62 %). Thrombocytosis was not observed in any patient. Relevant bone marrow features (n = 12) included hypercellularity (92 %) with marked granulopoiesis (92 %), nonclustered microlobulated megakaryocytes (83 %), and marrow fibrosis (83 %). Nine deaths (progression to secondary acute myeloid leukemia/blast phase, n = 7; cytopenia complications, n = 2) were recorded. Three-year survival rate was 27 %, possibly indicating poor prognosis of CBL mutated MDS/MPN patients.

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Acknowledgments

This work was supported by the “Deutsche José Carreras Leukämie-Stiftung e.V.” (AR R09/29f), Germany. The authors would like to thank Iris Palme and Carolin Hölting, Universitätsmedizin Mannheim, for technical support.

Authorship and disclosure

JS, TE, PE, JR, NCPC, and MM performed the laboratory work for the study; AH, AR, SS, TH, GM, NCPC, and WKH provided patient material; PS reviewed the bone marrow biopsies; JS and AR wrote the paper; AH, NCPC, and WKH revised the manuscript.

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Authors and Affiliations

  1. III. Medizinische Klinik, Universitätsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany

    Juliana Schwaab, Philipp Erben, Georgia Metzgeroth, Max Mossner, Wolf-Karsten Hofmann & Andreas Reiter

  2. Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany

    Thomas Ernst, Jenny Rinke & Andreas Hochhaus

  3. Münchner Leukämie Labor GmbH, Munich, Germany

    Susanne Schnittger & Torsten Haferlach

  4. Pathologisches Institut, Universitätsmedizin Mannheim, Mannheim, Germany

    Philipp Ströbel

  5. Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK

    Nicholas C. P. Cross

  6. Faculty of Medicine, University of Southampton, Southampton, UK

    Nicholas C. P. Cross

Authors
  1. Juliana Schwaab
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  2. Thomas Ernst
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  3. Philipp Erben
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  4. Jenny Rinke
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  5. Susanne Schnittger
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  6. Philipp Ströbel
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  7. Georgia Metzgeroth
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  8. Max Mossner
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  9. Torsten Haferlach
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  10. Nicholas C. P. Cross
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  11. Andreas Hochhaus
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  12. Wolf-Karsten Hofmann
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  13. Andreas Reiter
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Corresponding author

Correspondence to Andreas Reiter.

Additional information

Juliana Schwaab and Thomas Ernst contributed equally to this study.

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Schwaab, J., Ernst, T., Erben, P. et al. Activating CBL mutations are associated with a distinct MDS/MPN phenotype. Ann Hematol 91, 1713–1720 (2012). https://doi.org/10.1007/s00277-012-1521-3

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  • DOI: https://doi.org/10.1007/s00277-012-1521-3

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