| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Institut National de la Santé et de la Recherche Médicale U 764, Université Paris XI, Laboratoire d’Hématologie, Service de Médecine Interne-Immunologie, Hôpital Antoine Beclère, Clamart, France;
Laboratoire d’Onco-Hématologie, Commissariat à l’Energie Atomique/Direction des Sciences du Vivant, Fontenay aux Roses, France; and
Service d’Hématologie, Hôpital Pitié-Salpetrière, Paris, France
Chronic lymphocytic leukemia (CLL) results in the accumulation of B cells, presumably reflecting the selection of malignant cell precursors with Ag combined with complex alterations in protein activity. Repeated BCR stimulation of normal B cells leads to anergy and CD5 expression, both of which are features of CLL. Because CD5 is phosphorylated on tyrosine following BCR engagement and negatively regulates BCR signaling in normal B cells, we investigated its phosphorylation status and found it to be naturally phosphorylated on tyrosine but not on serine residues in CLL samples. To analyze the role of CD5, we established a B cell line in which CD5 is phosphorylated. Gene profiling of vector vs CD5-transfected B cells pointed out gene groups whose expression was enhanced: Apoptosis inhibitors (BCL2), NF-
B (RELB, BCL3), Wnt, TGF
, VEGF, MAPKs, Stats, cytokines, chemokines (IL-10, IL-10R, IL-2R, CCL-3, CCL-4, and CCR7), TLR-9, and the surface Ags CD52, CD54, CD70, and CD72. Most of these gene groups are strongly expressed in CLL B cells as compared with normal B cells. Unexpectedly, metabolic pathways, namely cholesterol synthesis and adipogenesis, are also enhanced by CD5. Conversely, CD5 inhibited genes involved in RNA splicing and processing, ribosome biogenesis, proteasome, and CD80 and CD86 Ags, whose expression is low in CLL. Comparison of CD5- vs tailless CD5-transfected cells further demonstrated the role of CD5 phosphorylation in the regulation of selected genes. These results support a model where CLL cells are chronically stimulated, leading to CD5 activation and cell survival. In addition to CD5 itself, we point to several CD5-induced genes as potential therapeutic targets.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordancRe with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a 2005 grant from Association de Recherche sur le Cancer to A.D.
2 H.G.-G., and A.S.-P. contributed equally to the work.
3 Address correspondence and reprint requests to Dr. Ali Dalloul, Institut National de la Santé et de la Recherche Médicale U 764, 32 Rue des Carnets, France. E-mail address: ali.dalloul{at}u-psud.fr
4 Abbreviations used in this paper: CLL, chronic lymphocytic leukemia; Ct, cycle threshold; MAPP, microarray pathway profile; MCL, mantle cell lymphoma; MM, mismatch; PM, perfect match.
5 The online version of this article contains supplemental material.
This article has been cited by other articles:
|
|
 |
|
  S. Garaud, C. Le Dantec, C. Berthou, P. M. Lydyard, P. Youinou, and Y. Renaudineau Selection of the Alternative Exon 1 from the cd5 Gene Down-Regulates Membrane Level of the Protein in B Lymphocytes J. Immunol., August 1, 2008; 181(3): 2010 - 2018. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
