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Chronic Myeloproliferative Neoplasias

Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event

Leukemia volume 29, pages 1115–1122 (2015)Cite this article

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Abstract

To explore the molecular profile and its prognostic implication in systemic mastocytosis (SM), we analyzed the mutation status of granulocyte–macrophage colony-forming progenitor cells (CFU-GM) in patients with KIT D816V+ indolent SM (ISM, n=4), smoldering SM (SSM, n=2), aggressive SM (ASM, n=1), SM with associated clonal hematologic non-mast cell lineage disorder (SM-AHNMD, n=5) and ASM-AHNMD (n=7). All patients with (A)SM-AHNMD (n=12) carried 1–4 (median 3) additional mutations in 11 genes tested, most frequently TET2, SRSF2, ASXL1, CBL and EZH2. In multi-mutated (A)SM-AHNMD, KIT D816V+ single-cell-derived CFU-GM colonies were identified in 8/12 patients (median 60%, range 0–95). Additional mutations were identified in CFU-GM colonies in all patients, and logical hierarchy analysis indicated that mutations in TET2, SRSF2 and ASXL1 preceded KIT D816V. In ISM/SSM, no additional mutations were detected and CFU-GM colonies were exclusively KIT D816V−. These data indicate that (a) (A)SM-AHNMD is a multi-mutated neoplasm, (b) mutations in TET2, SRSF2 or ASXL1 precede KIT D816V in ASM-AHNMD, (c) KIT D816V is thus a phenotype modifier toward SM and (d) KIT D816V or other mutations are rare in CFU-GM colonies of ISM/SSM patients, which might explain at least in part their better prognosis.

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Acknowledgements

This work was supported by the ‘Deutsche José Carreras Leukämie-Stiftung e.V.’ (grant no. DJCLSR 11/03 and 13/05) and the Austrian Science Fund (FWF) grant SFB F4704-B20. The authors thank S Uhlig and B Schleider for excellent technical assistance.

Author Contributions

MJ, JS, S Schnittger, KS, H-PH, S Schneider, NN, TH, AF and AR performed the laboratory work for the study. NM, GM, W-KH, PV and AR provided patient material and information. H-PH, KS and CW reviewed the bone marrow biopsies. MJ, JS, S Schnittger, KS, PV, W-KH, NCPC, AF and AR wrote the paper.

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Author notes

  1. M Jawhar and J Schwaab: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany

    M Jawhar, J Schwaab, G Metzgeroth, N Müller, N Naumann, W-K Hofmann, A Fabarius & A Reiter

  2. Munich Leukemia Laboratory, Munich, Germany

    S Schnittger & T Haferlach

  3. Department of Pathology, Ludwig-Maximilians-University, Munich, Germany

    K Sotlar, H-P Horny & C Walz

  4. Department of Clinical Chemistry, University Hospital Mannheim, Mannheim, Germany

    S Schneider

  5. Division of Hematology and Ludwig Boltzmann Cluster Oncology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria

    P Valent

  6. Wessex Regional Genetics Laboratory, Salisbury, UK

    N C P Cross

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

    N C P Cross

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Correspondence to A Reiter.

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S Schnittger and TH have equity ownership of MLL Munich Leukemia Laboratory GmbH. The remaining authors declare no competing financial interests.

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Jawhar, M., Schwaab, J., Schnittger, S. et al. Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event. Leukemia 29, 1115–1122 (2015). https://doi.org/10.1038/leu.2015.4

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