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Chronic Lymphocytic Leukemia

E2A is a transcriptional regulator of CD38 expression in chronic lymphocytic leukemia

Leukemia volume 25, pages 479–488 (2011)Cite this article

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Abstract

CD38, a nucleotide-metabolizing ectoenzyme and a receptor, is a negative prognostic marker for chronic lymphocytic leukemia (CLL) patients. CD38 has a genetic polymorphism, with a C → G variation in a putative E-box located in a regulatory region. E2A, the predominant E-box factor in B lymphocytes, was found to be highly expressed by CD38+ CLL patients. The highest CD38 levels scored by E2A+/G carrier patients suggested that E2A is (i) directly associated with CD38 expression, and that (ii) the binding of the transcription factor is influenced by the CD38 genotype. Chromatin immunoprecipitation indicated that E2A directly interacts with the CD38 regulatory region. Furthermore, E2A binding was stronger in the presence of the G allele. Experiments of E2A silencing led to a significant reduction of surface levels of CD38, confirming the working hypothesis. A direct functional interplay between E2A and CD38 was shown by exposing CLL cells to interleukin-2 and TLR-9 ligands, both inducers of CD38 expression. Under these conditions, CD38 upregulation was primarily conditioned by the presence of E2A and then by the G allele. The results of this study link E2A and CD38 expression within a common pathway, in which E-protein activity is required for the efficient induction of CD38 transcription.

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Acknowledgements

We thank Dr E Ferrero (University of Turin, Italy) and Dr D Colomer (Hospital Clinic, Barcelona, Espana) for expert advice and assistance in setting up the experiments. The expertize of K Gizzi and F Cottino is also gratefully acknowledged. We thank Aczon srl (Bologna, Italy) for labeling monoclonal antibodies produced by the Lab of Immunogenetics. This work was supported by the Associazione Italiana Ricerca Cancro (AIRC, IG8590 and Special Program Molecular and Clinical Oncology, 5 per Mille project), the Compagnia SanPaolo, Ministero della Salute—Bando Giovani Ricercatori 2008, Ministero della Università e Ricerca—Bando Futuro in Ricerca 2009, Progetti Ricerca Interesse Nazionale (PRIN) and the Regione Piemonte. The Fondazione Internazionale Ricerche Medicina Sperimentale (FIRMS) provided financial and administrative assistance.

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Authors and Affiliations

  1. Department of Genetics, Laboratory of Immunogenetics, Biology and Biochemistry, University of Turin Medical School, Turin, Italy

    I Saborit-Villarroya, T Vaisitti, F Malavasi & S Deaglio

  2. Human Genetics Foundation (HuGeF), Turin, Italy

    T Vaisitti & S Deaglio

  3. Division of Hematology, Department of Clinical and Experimental Medicine and BRMA, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    D Rossi & G Gaidano

  4. Division of Hematology, IRCCS ‘Casa Sollievo della Sofferenza’ Hospital, San Giovanni Rotondo, Italy

    G D'Arena

  5. Research Center for Experimental Medicine (CeRMS), Turin, Italy

    F Malavasi

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  1. I Saborit-Villarroya
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Correspondence to S Deaglio.

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Saborit-Villarroya, I., Vaisitti, T., Rossi, D. et al. E2A is a transcriptional regulator of CD38 expression in chronic lymphocytic leukemia. Leukemia 25, 479–488 (2011). https://doi.org/10.1038/leu.2010.291

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