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Annals of Hematology

, Volume 91, Issue 11, pp 1713–1720 | Cite as

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

  • Juliana Schwaab
  • Thomas Ernst
  • Philipp Erben
  • Jenny Rinke
  • Susanne Schnittger
  • Philipp Ströbel
  • Georgia Metzgeroth
  • Max Mossner
  • Torsten Haferlach
  • Nicholas C. P. Cross
  • Andreas Hochhaus
  • Wolf-Karsten Hofmann
  • Andreas ReiterEmail author
Original Article

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.

Keywords

CBL Point mutations MDS/MPN Clinical phenotype 

Notes

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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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Juliana Schwaab
    • 1
  • Thomas Ernst
    • 2
  • Philipp Erben
    • 1
  • Jenny Rinke
    • 2
  • Susanne Schnittger
    • 3
  • Philipp Ströbel
    • 4
  • Georgia Metzgeroth
    • 1
  • Max Mossner
    • 1
  • Torsten Haferlach
    • 3
  • Nicholas C. P. Cross
    • 5
    • 6
  • Andreas Hochhaus
    • 2
  • Wolf-Karsten Hofmann
    • 1
  • Andreas Reiter
    • 1
    Email author
  1. 1.III. Medizinische KlinikUniversitätsmedizin MannheimMannheimGermany
  2. 2.Klinik für Innere Medizin IIUniversitätsklinikum JenaJenaGermany
  3. 3.Münchner Leukämie Labor GmbHMunichGermany
  4. 4.Pathologisches InstitutUniversitätsmedizin MannheimMannheimGermany
  5. 5.Wessex Regional Genetics LaboratorySalisbury District HospitalSalisburyUK
  6. 6.Faculty of MedicineUniversity of SouthamptonSouthamptonUK

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