|
|
Blood, 15 January 2008, Vol. 111, No. 2, pp. 846-855.
Prepublished online as a Blood First Edition Paper on October 10, 2007; DOI 10.1182/blood-2007-05-089037.
 Previous Article | Next Article 
Submitted May 7, 2007
Accepted October 8, 2007
The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B-cells
Pablo G Longo, Luca Laurenti, Stefania Gobessi, Simona Sica, Giuseppe Leone, and Dimitar G Efremov*
ICGEB Molecular Hematology Group, Campus "A. Buzzati-Traverso", Rome, Italy
Hematology Institute, Universita Cattolica del Sacro Cuore, Rome, Italy
* Corresponding author; email: efremov{at}icgeb.org.
Sustained engagement of the B-cell receptor (BCR) increases apoptosis resistance in chronic lymphocytic leukemia (CLL) B-cells, whereas transient stimulation usually has an opposite effect. The anti-apoptotic BCR signal has been associated with prolonged activation of the PI3K/Akt and MEK/ERK pathways, which are key regulators of survival and proliferation in various cell types. To further define the relative contribution of the Akt and ERK kinases in regulating CLL B-cell survival, we introduced constitutively active mutants of Akt and MEK in primary CLL B-cells and evaluated changes in the expression of relevant pro- and anti-apoptotic proteins. Sustained activation of Akt resulted in increased leukemic cell viability and increased expression of the antiapoptotic proteins Mcl-1, Bcl-xL and XIAP, thus largely recapitulating the effects of sustained BCR stimulation. Constitutively active MEK2 also upregulated XIAP, but did not show a significant impact on leukemic cell survival. Downregulation of Mcl-1 by siRNA treatment induced rapid and potent apoptosis in CLL B-cells and blocked the antiapoptotic effect of sustained BCR stimulation, whereas downregulation of Bcl-xL and XIAP did not affect leukemic cell viability. These data demonstrate that Akt and Mcl-1 are major components of a survival pathway that can be activated in CLL B-cells by antigen 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]
|
|
|
|
|
|
|
J. L. Costantini, S. M. S. Cheung, S. Hou, H. Li, S. K. Kung, J. B. Johnston, J. A. Wilkins, S. B. Gibson, and A. J. Marshall
TAPP2 links phosphoinositide 3-kinase signaling to B-cell adhesion through interaction with the cytoskeletal protein utrophin: expression of a novel cell adhesion-promoting complex in B-cell leukemia
Blood,
November 19, 2009;
114(21):
4703 - 4712.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. D. Shanafelt, T. G. Call, C. S. Zent, B. LaPlant, D. A. Bowen, M. Roos, C. R. Secreto, A. K. Ghosh, B. F. Kabat, M.-J. Lee, et al.
Phase I Trial of Daily Oral Polyphenon E in Patients With Asymptomatic Rai Stage 0 to II Chronic Lymphocytic Leukemia
J. Clin. Oncol.,
August 10, 2009;
27(23):
3808 - 3814.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. P. Quiroga, K. Balakrishnan, A. V. Kurtova, M. Sivina, M. J. Keating, W. G. Wierda, V. Gandhi, and J. A. Burger
B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406
Blood,
July 30, 2009;
114(5):
1029 - 1037.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Niedermeier, B. T. Hennessy, Z. A. Knight, M. Henneberg, J. Hu, A. V. Kurtova, W. G. Wierda, M. J. Keating, K. M. Shokat, and J. A. Burger
Isoform-selective phosphoinositide 3'-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach
Blood,
May 28, 2009;
113(22):
5549 - 5557.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Burger, M. P. Quiroga, E. Hartmann, A. Burkle, W. G. Wierda, M. J. Keating, and A. Rosenwald
High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation
Blood,
March 26, 2009;
113(13):
3050 - 3058.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Balakrishnan, J. A. Burger, W. G. Wierda, and V. Gandhi
AT-101 induces apoptosis in CLL B cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance
Blood,
January 1, 2009;
113(1):
149 - 153.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Y. H. Hallaert, A. Jaspers, C. J. van Noesel, M. H. J. van Oers, A. P. Kater, and E. Eldering
c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches
Blood,
December 15, 2008;
112(13):
5141 - 5149.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. P. Pallasch, A. Schulz, N. Kutsch, J. Schwamb, S. Hagist, H. Kashkar, A. Ultsch, C. Wickenhauser, M. Hallek, and C.-M. Wendtner
Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease
Blood,
November 15, 2008;
112(10):
4213 - 4219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Pepper, T. T. Lin, G. Pratt, S. Hewamana, P. Brennan, L. Hiller, R. Hills, R. Ward, J. Starczynski, B. Austen, et al.
Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers
Blood,
November 1, 2008;
112(9):
3807 - 3817.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Guarini, S. Chiaretti, S. Tavolaro, R. Maggio, N. Peragine, F. Citarella, M. R. Ricciardi, S. Santangelo, M. Marinelli, M. S. De Propris, et al.
BCR ligation induced by IgM stimulation results in gene expression and functional changes only in IgVH unmutated chronic lymphocytic leukemia (CLL) cells
Blood,
August 1, 2008;
112(3):
782 - 792.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
