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Chronic lymphocytic leukemia

NOTCH1-mutated chronic lymphocytic leukemia cells are characterized by a MYC-related overexpression of nucleophosmin 1 and ribosome-associated components

Leukemia volume 31, pages 2407–2415 (2017)Cite this article

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Abstract

In chronic lymphocytic leukemia (CLL), the mechanisms controlling cell growth and proliferation in the presence of NOTCH1 mutations remain largely unexplored. By performing a gene expression profile of NOTCH1-mutated (NOTCH1-mut) versus NOTCH1 wild-type CLL, we identified a gene signature of NOTCH1-mut CLL characterized by the upregulation of genes related to ribosome biogenesis, such as nucleophosmin 1 (NPM1) and ribosomal proteins (RNPs). Activation of NOTCH1 signaling by ethylenediaminetetraacetic acid or by coculture with JAGGED1-expressing stromal cells increased NPM1 expression, and inhibition of NOTCH1 signaling by either NOTCH1-specific small interfering RNA (siRNA) or γ-secretase inhibitor reduced NPM1 expression. Bioinformatic analyses and in vitro activation/inhibition of NOTCH1 signaling suggested a role of MYC as a mediator of NOTCH1 effects over NPM1 and RNP expression in NOTCH1-mut CLL. Chromatin immunoprecipitation experiments performed on NOTCH1 intracellular domain (NICD)-transfected CLL-like cells showed the direct binding of NOTCH1 to the MYC promoter, and transfection with MYC-specific siRNA reduced NPM1 expression. In turn, NPM1 determined a proliferation advantage of CLL-like cells, as demonstrated by NPM1-specific siRNA transfection. In conclusion, NOTCH1 mutations in CLL are associated with the overexpression of MYC and MYC-related genes involved in protein biosynthesis including NPM1, which are allegedly responsible for cell growth and/or proliferation advantages of NOTCH1-mut CLL.

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Acknowledgements

We thank Jon C Aster and Carl A Johnson (Harvard, Boston, MA, USA) for kindly providing key reagents for this study. This work was supported, in part, by the Associazione Italiana Ricerca Cancro (AIRC), Investigator Grants IG-17622 and Special Program Molecular Clinical Oncology 5 × 1000 No. 10007; Progetto Ricerca Finalizzata IRCCS Nos RF-2010-2307262 and RF-2011-02349712, Progetto Giovani Ricercatori Nos GR-2011-02347441, GR-2011-02346826, GR-2011-02351370, Ministero della Salute, Rome, Italy; Associazione Italiana contro le Leucemie, linfomi e mielomi (AIL), Venezia Section, Pramaggiore Group, Italy; Fondazione per la Vita di Pordenone, Italy; 5x1000 Intramural Program, Centro di Riferimento Oncologico, Aviano, Italy.

Author contributions

FP contributed to writing the manuscript, analyzed the data and performed the research, TB performed the research, EV, RB, PB, FMR, AZ, FS, DB, ET and MD contributed to perform the research, GDA, FDR, FZ, GP, GDP, DR, GG provided well-characterized biological samples and contributed to writing the manuscript, VG and MDB designed the study, interpreted data and wrote the manuscript.

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  1. V Gattei and M Dal Bo: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy

    F Pozzo, T Bittolo, E Vendramini, R Bomben, P Bulian, F M Rossi, A Zucchetto, E Tissino, M Degan, V Gattei & M Dal Bo

  2. Department of Onco-Hematology, IRCCS ‘Centro di Riferimento Oncologico della Basilicata’, Rionero in Vulture, Italy

    G D’Arena

  3. Division of Hematology, Ferrarotto Hospital, Catania, Italy

    F Di Raimondo

  4. Clinica Ematologica, Centro Trapianti e Terapie Cellulari ‘Carlo Melzi’ DISM, Azienda Ospedaliera Universitaria S Maria Misericordia, Udine, Italy

    F Zaja

  5. Department of Internal Medicine and Hematology, Maggiore General Hospital, University of Trieste, Trieste, Italy

    G Pozzato

  6. Hematology, Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

    D Rossi

  7. Department of Translational Medicine, Division of Hematology, University of Eastern Piedmont, Novara, Italy

    G Gaidano

  8. Division of Hematology, S Eugenio Hospital and University of Tor Vergata, Rome, Italy

    G Del Poeta

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  1. F Pozzo
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Pozzo, F., Bittolo, T., Vendramini, E. et al. NOTCH1-mutated chronic lymphocytic leukemia cells are characterized by a MYC-related overexpression of nucleophosmin 1 and ribosome-associated components. Leukemia 31, 2407–2415 (2017). https://doi.org/10.1038/leu.2017.90

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