Online citations, reference lists, and bibliographies.
← Back to Search

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.

P. G. Longo, L. Laurenti, S. Gobessi, S. Sica, G. Leone, D. Efremov
Published 2008 · Biology, Medicine

Cite This
Download PDF
Analyze on Scholarcy
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 antiapoptotic 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 antiapoptotic proteins. Sustained activation of Akt resulted in increased leukemic cell viability and increased expression of the antiapoptotic proteins Mcl-1, Bcl-xL, and X-linked inhibitor of apoptosis protein (XIAP), thus largely recapitulating the effects of sustained BCR stimulation. Constitutively active MEK2 also up-regulated XIAP, but did not show a significant impact on leukemic cell survival. Down-regulation 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 down-regulation 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.
This paper references
Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.
R. Damle (1999)
Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1 For personal use only
U Maurer (2006)
Molecular interpretation of ERK signal duration by immediate early gene products
Leon O. Murphy (2002)
Role of phosphatidylinositol 3'-kinase/AKT pathway in diffuse large B-cell lymphoma survival.
S. Uddin (2006)
Survival response to B-cell receptor ligation is restricted to progressive chronic lymphocytic leukemia cells irrespective of Zap70 expression.
Pierre-Antoine Deglesne (2006)
Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status.
C. I. Mockridge (2007)
Chronic lymphocytic leukemia: revelations from the B-cell receptor.
F. Stevenson (2004)
CD6 ligation modulates the Bcl-2/Bax ratio and protects chronic lymphocytic leukemia B cells from apoptosis induced by anti-IgM.
L. M. Osorio (1997)
ZAP-70 enhances B-cell-receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells.
S. Gobessi (2007)
Efficient nucleofection of primary human B cells and B-CLL cells induces apoptosis, which depends on the microenvironment and on the structure of transfected nucleic acids
M. Seiffert (2007)
Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1.
U. Maurer (2006)
Critical Role of Endogenous Akt/IAPs and MEK1/ERK Pathways in Counteracting Endoplasmic Reticulum Stress-induced Cell Death*
P. Hu (2004)
Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse
P. Costello (2002)
PI3K and Btk differentially regulate B cell antigen receptor-mediated signal transduction
H. Suzuki (2003)
Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1.
I. Pedersen (2002)
Cell Death Critical Control Points
N. Danial (2004)
Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia
B. Carter (2003)
The costimulation-regulated duration of PKB activation controls T cell longevity
Jianxun Song (2004)
Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737.
Victoria Del Gaizo Moore (2007)
CD38 expression distinguishes two groups of B-cell chronic lymphocytic leukemias with different responses to anti-IgM antibodies and propensity to apoptosis.
S. Zupo (1996)
Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia.
L. Chen (2002)
Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia.
T. Hamblin (1999)
Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity.
H. Harada (2004)
Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia.
G. Tobin (2004)
Bryostatin and CD40‐ligand enhance apoptosis resistance and induce expression of cell survival genes in B‐cell chronic lymphocytic leukaemia
S. Kitada (1999)
Cancer Res
Activation of the MEK/MAPK pathway is involved in bryostatin1-induced monocytic differenciation and up-regulation of X-linked inhibitor of apoptosis protein.
H. Lin (2002)
Multiple Distinct Sets of Stereotyped Antigen Receptors Indicate a Role for Antigen in Promoting Chronic Lymphocytic Leukemia
B. Messmer (2004)
A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells For personal use only
S Cuni (2004)
Proliferation and Survival of Activated B Cells Requires Sustained Antigen Receptor Engagement and Phosphoinositide 3-Kinase Activation1
A. Donahue (2003)
Constitutively Activated Akt-1 Is Vital for the Survival of Human Monocyte-Differentiated Macrophages
H. Liu (2001)
ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia.
L. Chen (2005)
ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia.
L. Rassenti (2004)
VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia.
Y. Lee (2004)
Emerging role of Mcl-1 in actively counteracting BH3-only proteins in apoptosis
J. Zhuang (2006)
CD40 stimulation of B‐cell chronic lymphocytic leukaemia cells enhances the anti‐apoptotic profile, but also Bid expression and cells remain susceptible to autologous cytotoxic T‐lymphocyte attack
Arnon P. Kater (2004)
Mcl-1 Is a Relevant Therapeutic Target in Acute and Chronic Lymphoid Malignancies: Down-Regulation Enhances Rituximab-Mediated Apoptosis and Complement-Dependent Cytotoxicity
S. Hussain (2007)
Regulation of cell death protease caspase-9 by phosphorylation.
M. H. Cardone (1998)
Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses.
S. Kitada (1998)
Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells
D. Iglesias-Serret (2007)
Mcl‐1 and Bcl‐2/Bax ratio are associated with treatment response but not with Rai stage in B‐cell chronic lymphocytic leukemia
A. Saxena (2004)
A sustained activation of PI3K/NF-κB pathway is critical for the survival of chronic lymphocytic leukemia B cells
S. Cuni (2004)
Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling.
J. Pouyssegur (2003)
Akt Phosphorylation and Stabilization of X-linked Inhibitor of Apoptosis Protein (XIAP)*
H. C. Dan (2004)
Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells.
A. Petlickovski (2005)
The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease
P. G. Longo (2007)
Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: relationship to in vivo rituximab resistance.
R. Bannerji (2003)
Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia
A. Rosenwald (2001)
Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1
J. Opferman (2003)
ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia.
M. Crespo (2003)
Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia.
S. Lanham (2003)
Recent advances in the molecular biology and immunobiology of chronic lymphocytic leukemia.
M. Ferrarini (2004)
Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins.
G. Widhopf (2004)
Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery
S. Datta (1997)
Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity.
L. Smit (2007)

This paper is referenced by
Biology of Chronic Lymphocytic Leukemia in Different
Yair Herishanu (2013)
The role of AKT during IL-3-dependent survival signalling
Benjamin Green (2014)
Advances in Chronic Lymphocytic Leukemia
S. Malek (2013)
Molecular Characterization of Chronic Lymphocytic Leukemia Patients with a High Number of Losses in 13q14
A. E. Rodríguez (2012)
Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer.
Mariya O. Krisenko (2015)
Idelalisib: First-in-Class PI3K Delta Inhibitor for the Treatment of Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia, and Follicular Lymphoma
Q. Yang (2015)
Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies
E. Jabbour (2014)
Evaluation of MiR-15a and MiR-16-1 as prognostic biomarkers in chronic lymphocytic leukemia.
T. Braga (2017)
Reconstitution of PTEN activity by CK2 inhibitors and interference with the PI3-K/Akt cascade counteract the antiapoptotic effect of human stromal cells in chronic lymphocytic leukemia.
M. Shehata (2010)
CD markers variations in chronic lymphocytic leukemia: New insights into prognosis
T. Vosoughi (2019)
8 Pathophysiology of Protein Kinase C Isozymes in Chronic Lymphocytic Leukaemia
J. C. Allen (2017)
Preliminary Characterisation of FAM129C, a Novel Protein Identified from Proteomic Screening of CLL Samples
R. Walewska (2011)
OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells.
T. Liu (2015)
Role of spleen tyrosine kinase in the pathogenesis of chronic lymphocytic leukemia
Gege Feng (2014)
Towards New Therapeutic Targets: Identification of Novel Tumor Markers in Chronic Lymphocytic Leukemia
Eva Mikaelsson (2010)
Effects of hyperthermia and HSP70 protein overexpression on FOXO3a levels in Acute Lymphoblastic T-cells
Lisette Verzijlenberg (2017)
Title: Targeting the mTORC2 signaling complex in B cell malignancies. Running Title: mTORC2 signaling in B cell malignancies
Wei Liao (2019)
Concepts of Chronic Lymphocytic Leukemia Pathogenesis: DNA Damage Response and Tumor Microenvironment
L. Frenzel (2016)
Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease.
C. Pallasch (2008)
Molecular Genetic and DNA Methylation Profiling of Chronic Lymphocytic Leukaemia : A Focus on Divergent Prognostic Subgroups and Subsets
N. Cahill (2012)
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.
J. Burger (2009)
A phase 2 study of ofatumumab (Arzerra®) in combination with a pan-AKT inhibitor (afuresertib) in previously treated patients with chronic lymphocytic leukemia (CLL)*
C. Chen (2019)
Researchitol 3-kinase inhibitor(LY294002) induces apoptosis of human nasopharyngeal carcinoma in vitro and in vivo
Hanguo Jiang (2010)
Molecular and cellular mechanisms of CLL: novel therapeutic approaches
L. Pleyer (2009)
c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches.
D. Y. H. Hallaert (2008)
The pleiotropic flavonoid quercetin: from its metabolism to the inhibition of protein kinases in chronic lymphocytic leukemia.
G. L. Russo (2014)
Etudes des altérations fonctionnelles de la signalisation dépendante du récepteur à l’antigène dans les cellules B de la Leucémie Lymphoïde Chronique
Maude Quettier (2015)
Emerging treatment options for patients with p53-pathway-deficient CLL
Marisa J L Aitken (2019)
BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts
S. Locatelli (2014)
Clinical translation of nuclear export inhibitors in cancer.
W. Senapedis (2014)
Epigenetic silencing of tumor suppressor miR-3151 contributes to Chinese chronic lymphocytic leukemia by constitutive activation of MADD/ERK and PIK3R2/AKT signaling pathways
L. Wang (2015)
Ex vivo study of the effect of an anti-proliferative drug in Chronic Lymphocytic Leukemia cells mimicking proliferative niches microenvironment
Meritxell Aguiló García (2013)
See more
Semantic Scholar Logo Some data provided by SemanticScholar