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Acute Leukemias

Molecular profiling of blastic plasmacytoid dendritic cell neoplasm reveals a unique pattern and suggests selective sensitivity to NF-kB pathway inhibition

Leukemia volume 28, pages 1606–1616 (2014)Cite this article

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Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease of controversial origin recently recognized as a neoplasm deriving from plasmacytoid dendritic cells (pDCs). Nevertheless, it remains an orphan tumor with obscure biology and dismal prognosis. To better understand the pathobiology of BPDCN and discover new targets for effective therapies, the gene expression profile (GEP) of 25 BPDCN samples was analyzed and compared with that of pDCs, their postulated normal counterpart. Validation was performed by immunohistochemistry (IHC), whereas functional experiments were carried out ex vivo. For the first time at the molecular level, we definitely recognized the cellular derivation of BPDCN that proved to originate from the myeloid lineage and in particular, from resting pDCs. Furthermore, thanks to an integrated bioinformatic approach we discovered aberrant activation of the NF-kB pathway and suggested it as a novel therapeutic target. We tested the efficacy of anti-NF-kB-treatment on the BPDCN cell line CAL-1, and successfully demonstrated by GEP and IHC the molecular shutoff of the NF-kB pathway. In conclusion, we identified a molecular signature representative of the transcriptional abnormalities of BPDCN and developed a cellular model proposing a novel therapeutic approach in the setting of this otherwise incurable disease.

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Acknowledgements

We thank Dr Guarguaglini at the pharmacy-compounding center of S. Orsola-Malpighi Hospital of Bologna, Italy for providing Bortezomib. This work was supported by AIRC (IG10519 and 5xMille10007, Prof Pileri), AIRC (IG 2013 N.14355, Prof Piccaluga), Centro Interdipartimentale per la Ricerca sul Cancro ‘G. Prodi’, BolognAIL, RFO (Prof Pileri, Prof Piccaluga), FIRB Futura 2011 (RBFR12D1CB; Prof Piccaluga), Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte e Ravenna, Progetto Strategico di Ateneo 2006 (Prof Pileri and Dr Piccaluga) and by MIUR (PRIN 2011, Prof Facchetti and Prof Pileri).

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Author notes

  1. M R Sapienza, F Fuligni, C Agostinelli, C Tripodo, S Righi, M A Laginestra, A Pileri, M Mancini, M Rossi, F Ricci, A Gazzola, F Melle, C Mannu, F Ulbar, M Arpinati, M Paulli, T Maeda, D Gibellini, L Pagano, N Pimpinelli, M Santucci, L Cerroni, C M Croce, F Facchetti, P P Piccaluga and S A Pileri: P P Piccaluga and S A Pileri: These authors contributed equally to this work.

  2. Members of the AIRC 5xMille consortium ‘Genetics-driven targeted management of lymphoid malignancies’ are listed before references.

Authors and Affiliations

  1. Department of Experimental, Diagnostic, and Specialty Medicine, Hematopathology & Hematology Sections, Molecular Pathology Laboratory, S. Orsola-Malpighi Hospital, Bologna University, Bologna, Italy

    M R Sapienza, F Fuligni, C Agostinelli, S Righi, M A Laginestra, M Mancini, M Rossi, A Gazzola, F Melle, C Mannu, F Ulbar, M Arpinati, P P Piccaluga & S A Pileri

  2. Department of Health Science, Tumour Immunology Unit, Human Pathology Section University of Palermo School of Medicine, Palermo, Italy

    C Tripodo

  3. Department of Surgery and Translational Medicine - Division Dermatology, University of Florence, Florence, Italy

    A Pileri Jr & N Pimpinelli

  4. Department of Hematology, Oncology and Laboratory Medicine, Transfusion Medicine Service, S. Orsola-Malpighi Hospital, Bologna, Italy

    F Ricci

  5. Anatomic Pathology Section, University of Pavia Medical School, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Policlinico, San Matteo, Pavia, Italy

    M Paulli

  6. Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    T Maeda

  7. Department of Experimental, Diagnostic, and Specialty Medicine, Microbiology Section, S. Orsola-Malpighi Hospital, Bologna University, Bologna, Italy

    D Gibellini

  8. Institute of Hematology, Catholic University, Rome, Italy

    L Pagano

  9. Department of Surgery and Translational Medicine, Pathologic Anatomy Division, University of Florence, Florence, Italy

    M Santucci

  10. Department of Dermatology, Medical University of Graz, Graz, Austria

    L Cerroni

  11. Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    C M Croce

  12. Department of Molecular and Translational Medicine, Pathology Section, University of Brescia, Brescia, Italy

    F Facchetti

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  1. M R Sapienza
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  2. F Fuligni
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for the AIRC 5xMille consortium ‘Genetics-driven targeted management of lymphoid malignancies’ and the Italian Registry on Blastic Plasmacytoid Dendritic Cell Neoplasm

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Correspondence to P P Piccaluga.

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Sapienza, M., Fuligni, F., Agostinelli, C. et al. Molecular profiling of blastic plasmacytoid dendritic cell neoplasm reveals a unique pattern and suggests selective sensitivity to NF-kB pathway inhibition. Leukemia 28, 1606–1616 (2014). https://doi.org/10.1038/leu.2014.64

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