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Chronic Lymphocytic Leukemia

The functional in vitro response to CD40 ligation reflects a different clinical outcome in patients with chronic lymphocytic leukemia

Leukemia volume 25, pages 1760–1767 (2011)Cite this article

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A Corrigendum to this article was published on 09 November 2011

This article has been updated

Abstract

Malignant B lymphocytes from chronic lymphocytic leukemia (CLL) patients maintain the capacity to respond to CD40 ligation, among other microenvironmental stimuli. In this study, we show that (i) leukemic CLL cells stimulated with the soluble form of CD40L in vitro show differential responses in terms of upregulation of surface markers (CD95 and CD80) and induction of chemokines (CCL22 and CCL17) expression/secretion, and that (ii) these changes are mirrored by a distinct activation of intracellular signalling pathways including increase in IKKalpha/beta phosphorylation and upregulation of antiapoptotic proteins (BCL-2 and MCL-1). CLL patients can then be segregated into two distinct functional subsets. We defined the responsive subset of cases CD40L dependent, considering the capacity to respond as a sign of persistent need of this stimulation for the leukemic expansion. Conversely, we named the unresponsive cases CD40L independent, considering them less dependent on this microenvironmental signal, presumably because of a higher autonomous proliferative and survival potential. Importantly, we report that (iii) the two functional subsets show an opposite clinical outcome, with CD40L-independent cases having a shorter time to progression. This indicates that the functional differences observed in vitro may reflect a different leukemic potential in vivo likely responsible for a distinct clinical course.

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  • 09 November 2011

    This article has been corrected since advance Online Publication, and a corrigendum is also printed in this issue

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Acknowledgements

We thank Luisa Granziero, Paola Circosta, Massimo Geuna and Giuseppe Guida for helpful suggestions and technical support. This project was supported by: Associazione Italiana per la Ricerca sul Cancro AIRC (Investigator Grant and Special Program Molecular Clinical Oncology—5 per mille #9965), ‘CLLGRF—U.S./European Alliance for the Therapy of CLL’, FIRB and PRIN—Ministero Istruzione, Università e Ricerca (MIUR), Roma, Progetti Integrati Oncologia (PIO)—Ministero della Salute, Roma. CS is supported by the EHA Fellowship Program (2009/18), AJ is supported by a EHA Partner Fellowship Program.

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Author notes

  1. C Scielzo and B Apollonio: These authors equally contributed to this work.

Authors and Affiliations

  1. Division of Molecular Oncology, Laboratory of Lymphoid Malignancies, Istituto Scientifico San Raffaele, Milan, Italy

    C Scielzo, B Apollonio, M Muzio & F Caligaris-Cappio

  2. Unversità degli studi di Milano, Milan, Italy

    C Scielzo

  3. Università Vita-Salute San Raffaele, Milan, Italy

    B Apollonio, E ten Hacken, P Ghia & F Caligaris-Cappio

  4. Division of Molecular Oncology, Laboratory of cell activation and signalling, Istituto Scientifico San Raffaele, Milan, Italy

    B Apollonio & M Muzio

  5. Haematology Section, University of Ferrara, Ferrara, Italy

    L Scarfò

  6. Division of Molecular Oncology, Laboratory of B Cell Neoplasia, Istituto Scientifico San Raffaele, Milan, Italy

    L Scarfò, A Janus, E ten Hacken & P Ghia

  7. Department of Oncology, Unit of Lymphoid Malignancies, Istituto Scientifico San Raffaele, Milan, Italy

    P Ghia & F Caligaris-Cappio

  8. MAGIC (Microenvironment and Genes in Cancers of the blood) Interdivisional Research Program, Istituto Scientifico San Raffaele, Milan, Italy

    P Ghia & F Caligaris-Cappio

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  1. C Scielzo
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Correspondence to P Ghia.

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This article has been corrected since advance Online Publication, and a corrigendum is also printed in this issue

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Scielzo, C., Apollonio, B., Scarfò, L. et al. The functional in vitro response to CD40 ligation reflects a different clinical outcome in patients with chronic lymphocytic leukemia. Leukemia 25, 1760–1767 (2011). https://doi.org/10.1038/leu.2011.149

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