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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4820-4827. Prepublished online as a Blood First Edition Paper on February 22, 2005; DOI 10.1182/blood-2004-07-2669. This Article Full Text (PDF) Supplemental Tables All Versions of this Article: 2004-07-2669v1 105/12/4820    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Petlickovski, A. Articles by Efremov, D. G Search for Related Content PubMed PubMed Citation Articles by Petlickovski, A. Articles by Efremov, D. G Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 13, 2004 Accepted February 8, 2005 Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B-cells Aleksandar Petlickovski, Luca Laurenti, Xiaoping Li, Sara Marietti, Patrizia Chiusolo, Simona Sica, Giuseppe Leone, and Dimitar G Efremov* ICGEB Outstation - Monterotondo, CNR Campus "Adriano Buzzati-Traverso", Rome, Italy Hematology Institute, Universita Cattolica del Sacro Cuore, Rome, Italy * Corresponding author; email: efremov{at}icgeb.org. The clinical course of chronic lymphocytic leukemia (CLL) differs significantly between patients with mutated (M-CLL) and unmutated (U-CLL) immunoglobulin VH genes, implying a role for B-cell receptor (BCR) signaling in the pathogenesis of this disease. We have now investigated activation of downstream BCR signaling pathways in U-CLL and M-CLL B-cells using soluble (sol-IgM) and immobilized (imm-IgM) anti-IgM antibodies as models for antigenic stimulation. Ligation of the BCR with sol-IgM induced incomplete responses in both CLL subsets, resembling the pattern described for tolerant B-cells. This response was characterized by transient phosphorylation of ERK and Akt, lack of activation of JNK and p38 MAPK, and variable activation of PLC2 and NF-B. Stimulation with imm-IgM elicited a more complete BCR signal and significantly prolonged phosphorylation of Erk and Akt, indicating persistent or repetitive BCR signaling. Moreover, this type of stimulation increased the levels of the anti-apoptotic protein Mcl-1 and protected from chemotherapy-induced apoptosis, whereas induction of apoptosis and downregulation of Mcl-1 was observed following stimulation with sol-IgM. These data demonstrate that only sustained BCR signaling can promote survival of CLL B-cells and indicate that the main difference between CLL with mutated and unmutated VH genes may reside in the availability of such stimulation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Herling, K. A. Patel, N. Weit, N. Lilienthal, M. Hallek, M. J. Keating, and D. Jones High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia Blood, November 19, 2009; 114(21): 4675 - 4686. [Abstract] [Full Text] [PDF] A. M. McElligott, E. N. Maginn, L. M. Greene, S. McGuckin, A. Hayat, P. V. Browne, S. Butini, G. Campiani, M. A. Catherwood, E. Vandenberghe, et al. The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia Cancer Res., November 1, 2009; 69(21): 8366 - 8375. 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