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BCL2L1 (BCL2-like 1)
Mariana Varna, Philippe Ratajczak, Philippe Bertheau, Anne Janin
U728-INSERM/Paris 7 Paris Diderot, 1 avenue Claude Vellefaux, 75010 Paris, France (MV, PR); U728INSERM/Paris 7 Paris Diderot, Hopital Saint Louis-Service de Pathologie, 1 avenue Claude Vellefaux,
75010 Paris, France (PB, AJ)
Published in Atlas Database: December 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/BCL2L1ID129ch20q11.html
DOI: 10.4267/2042/44848
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Description
Identity
Bcl2L1 DNA contains 58394 bps (genomic size) and
RNA 2575 bps. Bcl2L1, member of the Bcl-2 protein
family, plays a role in the regulation of apoptosis. Two
major isoforms exist due to alternative splicing of the
BCL2L1 mRNA: Bcl-xS and Bcl-xL.
The bcl-x promoter contains consensus motifs for a
number of transcription factors, as Sp1, AP-1, Oct-1,
Ets, Rel/NF-kB, STATs, and GATA-1, in which three
transcription factor families, STATs, Rel/NF-kB, and
Ets family, have been demonstrated to play an
important role in the regulation of bcl-x gene
expression (Grillot et al., 1997). Bcl-xS has 3 exons
(contains exon2b shortly than 2a), and forms a
heterodimer with bcl2 to promoting apoptosis.
Bcl-xL has 4 exons (contains exon 2a) and form
heterodimer with Bax, Bak and has cell death
repressing activity (Tamura et al., 2009).
Bcl-xL protein can be regulated post-transcriptionally
and it is mainly controlled at the gene expression level
(Grad et al., 2000). Bcl-xL protects cells from
apoptosis by regulating mitochondria membrane
potential by interacting with pro-apoptotic members
Bax or Bim and subsequently prevents the release of
cytochrome C. Bcl-xL protein displays remarkable
amino acid and structural homology to Bcl-2
(González-García et al., 1994).
At the post-translational level, BCL-xL is
phosphorylated by SAPK/JNK after exposure to
microtubule-damaging drugs (Poruchynsky et al., 1998;
Basu et al., 2003). Bcl-xL resides in the nuclear
envelope, extra-nuclear membranes, including the
mitochondrion but also cytosol (González-García et al.,
1994).
Other names: BCL-XL/S; BCL2L; BCLX; Bcl-X;
Bcl2-L-1; DKFZp781P2092; bcl-xL; bcl-xS
HGNC (Hugo): BCL2L1
Location: 20q11.21
Local order: According to GeneLoc and NCBI Map
Viewer, genes flanking BCL2L11 in plus strand
direction are: COX4I2 (20q11.21; cytochrome c
oxidase subunit IV isoform 2 (lung)); MYLK2
(20q11.21; myosin light chain kinase 2).
Note: The Bcl2L1 proteins are encoded by BCL2L1
gene. Bcl2L1 proteins belong to the BCL-2 protein
family; the members of this family form hetero- or
homodimers and act as anti- or pro-apoptotic regulators
that are involved in a wide variety of cellular activities.
Bcl2L1 proteins are located outer mitochondrial
membrane, and have been shown to regulate
mitochondrial membrane channel (VDAC) opening.
VDAC regulates mitochondrial membrane potential,
and thus controls the production of reactive oxygen
species and release of cytochrome C by mitochondria,
both of which are the potent inducers of cell apoptosis.
DNA/RNA
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Polymorphism
In a study of 105 patients with multiple slerosis
relapsing disease it was identified sequence alterations
in the promoter region BCL-X gene (Kuhlmann et al.,
2002).
and PGAM5 (12q24.33; phosphoglycerate mutase
family member 5).
Like Bcl-xL, Bcl-x(beta) binds to the pro-apoptotic
protein Bax, suggesting a functional activity in vivo
(Ban et al., 1998).
Protein
Expression
The expression of Bcl-xL and Bcl-xS appeared
differentially regulated in human tissues. Bcl-xS is
expressed at high levels in cells that undergo a high rate
of turnover, such as developing lymphocytes. In
contrast, Bcl-xL is found in tissues containing longlived postmitotic cells, such as adult brain (Boise et al.,
1993).
Description
Three alternatively transcript variants, which encode
distinct isoforms, have been reported. The longer
isoform Bcl-xL acts as an apoptotic inhibitor and the
shorter form Bcl-xS acts as an apoptotic activator
(Boise et al., 1993). The last one Bcl-x(beta) differs
from the longer and the shorter forms by a modification
of the last 45 amino acids (Ban et al., 1998).
The BH1 and BH2 motifs are required for both
heterodimerization with other Bcl-2 family members,
and for repression of cell death. The BH4 motif is
required for anti-apoptotic activity.
Thus, Bcl-xL forms homodimers and heterodimers with
Bak (6p21.31; BCL2-antagonist/killer 1) isoform
Sigma, Bax (19q13.33; BCL2-associated X protein)
and Bcl2 (18q21.3; B-cell leukemia/lymphoma 2).
Heterodimerization with Bax does not seem to be
required for anti-apoptotic activity. Also interacts with
Bad (11q13.1; BCL2-antagonist of cell death), Bbc3
(19q13.3-q13.4; BCL2 binding component 3), Siva
isoform 1 (14q32.33), BCL2L11 (2q13; BCL2-like 11
(apoptosis facilitator)), BECN1 (17q21.31; Beclin-1),
Localisation
Bcl-xL resides in the nuclear envelope, extra-nuclear
membranes, including the mitochondrion but also
cytosol (González-García et al., 1994).
Function
The Bcl-xL isoform is a potent inhibitor of cell death.
Its association with SIVA-1 inhibits its anti-apoptotic
activity (Chu et al., 2004). The binding of this isoform
to the voltage-dependent anion channel (VDAC)
regulates cell death by blocking it and preventing the
release of the cytochrome into the cytoplasm (Vander
Heiden et al., 2001; Malia et al., 2007). In contrast to
Bcl-xL isoform, the Bcl-xS isoform promotes
apoptosis.
BCL2L1 proteins
Longer isoform: Bcl-xL 233 aa
Shorter isoform: Bcl-xS 170 aa
Alternative isoform: Bcl-x(beta) 227 aa
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Bcl-xL secondary structure: Full lengh Bcl-xL protein comports 9 helix and 1 turn domains.
Bcl-xS induces apoptosis in a caspase- and BH3dependent manner by a mechanism involving
cytochrome c release. BAK and BAX can be involved
in Bcl-xS induced apoptosis (Kim et al., 2004;
Lindenboim et al., 2005).
Bcl-xL mutants correlate with their ability to form
homodimers (Jeong et al., 2004).
chemotherapeutic drug-induced apoptosis (SchulzeBergkamen et al., 2008). In another study using
pancreatic, prostate and leukemic cells treated with
benzylisothiocyanate Bcl-xL was phosphorylated and
in parallel an enhancement of apoptosis (Basu et al.,
2008). In HepG2 cells treated with topotecan it was
shown that the expression of Bcl-xL was
simultaneously down-regulated with the up-regulation
of Bcl-xS in cytoplasm, which could explain the
induction of apoptosis (Zhang et al., 2008). Bcl-2 and
Bcl-xL inhibit apoptosis induced by a variety of agents
in MCF-7 cells. MCF-7 cell lines expressing Bcl-xL
and Bcl-2 were protected against apoptosis induced by
TNFa and doxorubicin (Fiebig et al., 2006).
PUMA (19q13.3-q13.4; p53-upregulated modulator of
apoptosis) interacts with anti-apoptotic Bcl-2 and BclxL and is dependent on Bax to induce apoptosis.
PUMA initiates apoptosis in part by dissociating Bax
and Bcl-xL, thereby promoting Bax multimerization
and mitochondrial translocation (Ming et al., 2006).
Mutations
Note
Few mutations are described. Thus, in 50 nonHodgkin's lymphoma cases it was found one missense
mutation in a patient with diffuse large B-cell
lymphoma. Sequence analysis of this case showed that
AGC (Ser) was mutated to GGC (Gly) in codon 154
(Yamaguchi et al., 2002). In one case of follicular
lymphoma mutation analysis revealed one synonymus
mutation (Codon 109 ACA-->ACC) (Liu et al., 2006).
The experimentally mutagenesis is described on:
Uniprot.
Autophagy
Implicated in
Note
It was shown that in normal conditions, Beclin 1
(17q21.31; autophagy related) is bound to and inhibited
by Bcl-2 or the Bcl-xL. This interaction involves a BH3
domain in Beclin 1 and the BH3 binding groove of Bcl2/Bcl-xL. But other proteins containing BH3 domains,
called BH3-only proteins, can competitively disrupt the
interaction between Beclin 1 and Bcl-2/Bcl-xL to
induce autophagy (Levine et al., 2008). The
overexpression of Bcl-xL enhances autophagic cell
death when apoptotic cell death is inhibited in Bax(-/)/Bak(-/-) double knockout cells (Kim, 2005).
Antiapoptotic role
Note
BCL-xL has been shown to inhibit cell death induced
by a number of apoptotic stimuli including gamma
irradiation, glucocorticoids, and anti-CD3 treatment
(Boise et al., 1993; Chao et al., 1995; Chao et al.,
1997). Down regulating the basal level of BCL-xL by
RNA interference induces apoptosis in aged human
fibroblasts without further stress, indicates that Bcl-xL
is an important factor in cell-death control in old
fibroblasts (Rochette et al., 2008). This was described
in other cell type: in hepatocellular carcinoma cells
Hepg2 (Lei et al., 2006), in nasopharyngeal carcinoma
cells (Liu et al., 2005) or in esophageal cancer cells
(Xie et al., 2006). In colorectal carcinoma (CRC) cell
lines and in tissue it was shown that Bcl-xL contributes
to apoptosis resistance. Same authors demonstrated that
CRC cells with reduced Bcl-xL expression were more
sensitive towards oxaliplatin- irinotecan, and 5-FU
while, Bcl-xL plasmid transfection decreased
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
Quiescence regulation
Note
It was shown that Bcl-xL facilitate G0 quiescence by
decreasing RNA content and stabilization an upregulation of p27 protein (14q32.13; interferon, alphainducible protein 27) due to phosphorylation of p27 at
Ser(10) by the kinase Mirk (19q13.2) (Janumyan et al.,
2008). P27 protein upregulation could delay cell cycle
re-entring throught inhibition of Myc (8q24) activity
(Greider et al., 2002).
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cancer Bcl-xL expression was higher in cancerous
tissue than in normal tissue and it was associated with
the pathological grade and lymph node metastasis.
Furthermore, in vitro transfection with Bcl-xL siRNA
inhibited the colony formation and invasion ability of
human colon cancer cell line HT29 (Zhang et al.,
2008). Caco-2 colon cancer cells treated with Bcl-xL
antisense oligonucleotides in combination with IR or
cisplatin showed reduction of the Bcl-xL protein level
by almost 50% and increase of apoptosis and reduction
of cell proliferation suggesting that Bcl-xL is an
important factor contributing to the treatment resistance
(Wacheck et al., 2003). siRNA Bcl-xL specific could
knockdown Bcl-xL protein expression and inhibit
proliferation more effectively in 5-FU-resistant cells
than in 5-FU-sensitive cells (Zhu et al., 2005). Bcl-xL
was found correlated with Hif1 alpha (14q23.2;
hypoxia inducible factor 1, alpha subunit) in
moderately and poorly differentiated rectal and colonic
tumors (Wincewicz et al., 2007).
Senescence
Note
In human diploid fibroblasts it was demonstrated the
role of BCL-xL for pre-senescence state induction with
decline of the ability of genotoxic stress to induce
apoptosis. It was found that aged cells became
progressively more resistant to UV-induced apoptosis
with apoptosis reduction of 10-20 folds. In young cells,
the level of anti-apoptotic protein BCL-xL decrease
after UV irradiation while pro-apoptotic protein Bax
increases. The increase in Bax tracked the level of p53
BCL-xL is itself responsible for the pre-senescence
decline in the ability of a genotoxic stress to induce
apoptosis. Acquired apoptosis resistance at late passage
is associated with altered UVB-regulation of Bcl family
members. Bcl-xL is a major contributor to UV-induced
apoptosis resistance in older cells (Rochette et al.,
2008).
Human neural stem cells
Glioblastoma
Disease
Bcl-xL enhances dopaminergic neuron generation from
human neural stem cells and mouse embryonic stem
cells (Shim et al., 2004).
Oncogenesis
Using human cell line hNS1 cell line with v-myc
(8q24; v-myc myelocytomatosis viral oncogene
homolog) immortalized and non-immortalized it was
found that Bcl-xL controls the balance between the
generation of neurons and glia from differentiating
immortalized
and
non-immortalized
hNSCs
differentiation (Liste et al., 2007).
Oncogenesis
Bcl-xL mediated induction of CXCR8 in glioblastoma
cells, through a nuclear factor-kappa B-dependent
mechanism (Gabellini et al., 2008).
Renal cell carcinoma
Disease
The expression of Bcl2 and/or Bcl-xL in normal tissue
is low in normal kidney.
Oncogenesis
Renal cell carcinoma (RCC) expressing high levels of
Bcl-xL and/or Bcl2 do not show any apoptotic cells,
and conversely when the expression of these proteins
was not detected, apoptosis was highly present (Gobé
et al., 2002).
Cutaneous cell carcinoma
Disease
Squamous cell carcinoma, a non melanoma skin
cancer, is a common malignancy in the worldwide
Caucasian population. Keratocarcinoma is a common
neoplasm of the skin and is typically characterised by
rapid growth. These two forms are difficult to
distinguish by histology.
Oncogenesis
In a series of twenty five squamous carcinoma (SCC)
and sixty four keratocarcinoma (KA), stained for bclxL, the authors detected that the two lesions differed
significantly in expression of Bcl-xL which was present
in 84% of the SCC compared with only 15% in the KA
(Vasiljevic et al., 2009).
Pancreatic carcinoma
Oncogenesis
A study using 25 patients showed an inverse
association for the Bcl-xL score and apoptotic index.
Bcl2 and Bax protein levels did not show any
association with the apoptotic index and were
overexpressed in most of the pancreatic cancer samples
(Sharma et al., 2005).
Prostate carcinoma
Disease
Bcl-xL protein was detected in the epithelial cells of
normal prostate gland and prostate cancers.
Oncogenesis
Increased levels of Bcl-xL were found to be correlated
with higher grade indicating a possible role of Bcl-xL
in prostate cancer progression (Krajewski et al., 1994).
Interactions of Bcl-xL with Bax (19q13.33; BCL2associated X protein) and Bak (6p21.31; BCL2antagonist/killer 1) were evidenced in lysates from
high-grade prostate cancer tissues and Bcl-xL would
Colorectal cancers
Oncogenesis
Bcl-xL shows a strong correlation with TGF-beta1
(19q13.2, transforming growth factor, beta 1) and Bax
(19q13.33; BCL2-associated X protein) in colorectal
cancers especially in deeply invading cancers
(pT3+pT4) instead of superficially growing tumors
(pT1+pT2) (Sulkowski et al., 2009). In a study with
fifty-six pair tissue samples from patients with colon
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exert an inhibitory effect over Bak via
heterodimerization (Castilla et al., 2006) whereas
blocking Bcl-xL expression in prostate cancer cells
decreased cell proliferation (Vilenchik et al., 2002).
These interactions may provide mechanisms for
suppressing the activity of proapoptotic Bax and Bak in
prostate cancer cells and that Bcl-xL expression
contributes to androgen resistance and progression of
prostate cancer.
Breast cancer
Oncogenesis
Most breast cancer cells overexpress Bcl-xL and Bcl-2
(Simonian et al., 1997). Increased levels of Bcl-xL
expression were found in primary human breast
carcinomas, mainly in undifferentiated tumors
(Olopade et al., 1997; Sierra et al., 1998). Using
orthotopic xenograft tumors in nude mice obtained
from human breast cancer cells lines MDA-MB 435,
MDA-MB 468 and MCF-7 it was observed that the
overexpression of Bcl-2 or Bcl-xL influenced
tumorigenicity. Overexpression of Bcl-xL was
associated with the loss of apoptosis in breast cancer
cells in vivo (Fernández et al., 2002).
Lung carcinoma
Oncogenesis
Biopsies from 30 cases of squamous cell carcinoma of
the lung in stage III were assessed for the expression of
Bcl-2, Bcl-xL, TP53 (17p13; Tumor protein p53) and
Bax (19q13.33; BCL2-associated X protein) at the
mRNA protein levels and immunohistochemistry. The
apoptotic index correlated with Bax expression but not
with Bcl-2, Bcl-xL or p53 levels (Shabnam et al.,
2004).
Soft tissue sarcomas
Oncogenesis
In a study of eighty-two soft tissue sarcomas (STS), a
combined high Bad/Bcl-xL mRNA expression levels
revealed a 20-fold increase and a worse prognosis
(Köhler et al., 2002).
Cervix carcinoma
Disease
Invasive squamous cell carcinoma of the cervix is
mainly treated by radiation.
Oncogenesis
In 30 cases of invasive carcinoma cervix before and
after 10 Gy RT it was shown an increased apoptotic
cell death with the up-regulation of Bax (19q13.33;
BCL2-associated X protein), and down-regulation of
Bcl-xL, without any significant change in the levels of
Bcl-2 (Adhya et al., 2006).
Giant cell tumor of bone
Disease
Giant cell tumor of bone (GCTb) is a benign but locally
aggressive tumor that infrequently shows metastatic
spread to the lungs (Bertoni et al., 2003).
Oncogenesis
Using array comparative genomic hybridization
performed on 20 frozen tumor samples of GCTb, the
authors showed that the most frequent region of change
identified was amplification of a 1 Mbp region at
20q11.1, which contains BCL2L1 gene. These results
were confirmed by Southern blot (Smith et al., 2006).
Bladder cancer
Oncogenesis
In a study with 42 samples of bladder transitional cell
carcinoma Bcl-x overexpression was observed in
45.2% but this overexpression was not correlated with
recurrence or survival (Kirsh et al., 1998). In another
study on 72 patients with muscle-invasive bilharzial
squamous cell carcinoma of the urinary bladder, Bcl-xL
overexpression was associated with tumor progression
(Hameed et al., 2008).
Non-Hodgkin's lymphoma
Oncogenesis
In non-Hodgkin's lymphoma, Bcl-xL is overexpressed
when compared with normal B cells (Xerri et al.,
1999). Rituximab (Rituxan, IDEC-C2B8) has been
shown to sensitize non-Hodgkin's lymphoma (NHL)
cell lines to chemotherapeutic drug-induced apoptosis
and selectively down-regulated Bcl-xL (Jazirehi et al.,
2003). The down-regulation of Bcl-xL by Rituximab is
dependant on up-regulation of Raf kinase inhibitor
protein RKIP on the ERK1/ERK2 pathway (Jazirehi et
al., 2004). In a study of 15 patients with reactive
hyperplasia, BCL-xL was overexpressed in follicular
lymphoma. No significant rise of BCL-xL expression
was observed in 24 patients with T-cell lymphoma and
24 patients with a diffuse large B-cell lymphoma (Liu
et al., 2006). In another study of 50 non-Hodgkin's
lymphoma cases Bcl-xl one missense mutations of the
transcript in a patient with diffuse large B-cell
lymphoma was found. Sequence analysis of this case
showed that AGC (Ser) was mutated to GGC (Gly) in
Hepatocellular carcinoma
Oncogenesis
In a study using 33 hepatocellular carcinomas (HCC)
Bcl-xL overexpression was found in 63.6% cancer
specimens (Watanabe et al., 2004). In another study,
performed on 42 patients with HCC, it was shown that
Bcl-xL expression was present in cancerous and noncancerous tissue whereas elevated levels Bcl-xL were
found in tumor tissue in the cytoplasm and the nuclei
from two thirds of the patients (Watanabe et al., 2002).
Bcl-2 and bcl-xL may play an important role in
regulating the apoptosis of normal liver and HCC (Guo
et al., 2002).
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codon 154 with a possibly role in the tumorigenesis of
non-Hodgkin's lymphoma (Yamaguchi et al., 2002).
upstream of mitochondrial perturbation and involved de
novo synthesis of the anti-apoptotic protein BCL-xL,
which could be responsible for resistance to ABT-737.
After therapy with ABT-737-related inhibitors,
resistant CLL cells might develop in lymph nodes in
vivo and that treatment strategies targeting multiple
Bcl2 antiapoptotic members simultaneously may have
synergistic activity (Vogler et al., 2009).
Follicular lymphomas
Oncogenesis
In follicular lymphoma and primary cutaneous follicle
center lymphomas, bcl-xL gene overexpression was
linked to short overall survival times. In a study of 20
patients with primary cutaneous follicle center
lymphomas Bcl-xL expression is significantly higher in
biopsies of patients, who developed relapse or disease
progression later compared with patients who did not.
Higher levels of bcl-xL gene expression were
significantly correlated with shorter progression-free
survival. This suggesting that bcl-xL overexpression is
inversely correlated with progression-free survival
suggests that bcl-xL, through its anti-apoptotic effect,
might contribute to tumor cell survival (SoltaniArabshahi et al., 2009). In another study were analysed
27 samples of follicular lymphoma, bcl-xL gene
overexpression was linked to short overall survival
times (Zhao et al., 2004). Moreover, in follicular
lymphoma, high Bcl-xL level was associated with
multiple extranodal involvement, elevated lactate
dehydrogenase level, high-risk international prognostic
index and a short overall survival time. In one case of
follicular lymphoma mutation analysis revealed one
synonymus mutation (Codon 109 ACA-->ACC) (Liu et
al., 2006). In a recent study of follicular lymphoma, it
has been demonstrated that TRAIL was cytotoxic only
against follicular lymphoma B cells. The engagement
of CD40 by its ligand CD40 induces a rapid RNA and
protein up-regulation of c-FLIP and Bcl-xL. The
antiapoptotic signaling of CD40, which interferes with
TRAIL-induced apoptosis in follicular lymphoma B
cells, involves NF-kappaB-mediated induction of cFLIP and Bcl-xL which can respectively interfere with
caspase 8 activation or mitochondrial-mediated
apoptosis (Travert et al., 2008).
Acute lymphoblastic leukemia (ALL)
Oncogenesis
Dexamethasone (Dex) is a glucocorticoid inducing
apoptosis. Dex induced significant down-regulation of
the anti-apoptotic Bcl-2 family members Bcl-2 and
Bcl-xL. In 12 primary childhood ALL samples, Dexinduced apoptosis was associated with activation of
Bax and down-regulation of Bcl-2 and/or Bcl-xL
(Laane et al., 2007). The first study which has
demonstrated a role of Bcl-xL in childhood acute
lymphoblastic leukemia was published in 1997. The
expression and the regulation of Bcl-2, Bcl-xl, and Bax
has been correlated with p53 status and sensitivity to
apoptosis in childhood acute lymphoblastic leukemia
(Findley et al., 1997). The resistance to glucocorticoid
treatment is often associated with treatment failure in
children with acute lymphoblastic leukaemia (ALL). In
30 consecutive children with ALL treated with
prednisone, Bcl-2 and Bcl-xl protein in 28 samples.
Prednisone treatment induced a decrease in Bcl-2 and
Bcl-xl levels in 17 and 16 of the 28 patients,
respectively. A statistically significant decrease was
only observed for Bcl-xl protein expression in T
phenotype ALL, in the poor responder group and in
patients with >20000/mm(3) white cell count (WBC) at
diagnosis. This study suggested a role of Bcl-xl in the
mechanisms of protection of leukemic cells from
apoptosis induced by glucocorticoids (Casale et al.,
2003). In a series of 62 consecutive children, only the
good response to prednisone and the low intensity of
Bcl-xL expression were independent significant
prognostic factors (Casale et al., 2003).
Chronic lymphocytic leukemia
Oncogenesis
B cell chronic lymphocytic leukemia (B-CLL) cannot
be cured with conventional chemotherapy because BCLL cells are resistant to programmed cell death and
arrested in G0/G1 phase of the cell cycle. In B-CLL
cells, levels of the anti-apoptotic Bcl-xL showed a
positive correlation with levels of the 80 kDa
regulatory component (Ku80) of the DNA-dependent
protein kinase that is involved in DNA double-stranded
break repair (Klein et al., 2000). It has also been
demonstrated in B-CLL that CD40 stimulation
enhanced the constitutive anti-apoptotic profile of BCLL cells by upregulation of Bcl-xL. Functionally,
CD40-stimulated B-CLL cells became resistant to
drug-induced apoptosis (Kater et al., 2004). More
recently, in 60 chronic lymphocytic leukemias (CLL)
treated with ABT-737 and its orally active analog,
ABT-263, revealed that the resistance occurred
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
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