Seminars in Cancer Biology 20 (2010) 424430

Contents lists available at ScienceDirect

Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Review

Chemokines and chemokine receptors in chronic lymphocytic leukemia (CLL):

From understanding the basics towards therapeutic targeting
Jan A. Burger
Department of Leukemia, Unit 428, The University of Texas M.D. Anderson Cancer Center, PO Box 301402, Houston, TX 77230, USA

a r t i c l e

i n f o

Keywords:
CLL
Chemokines
Chemokine receptors
CXCR4
Plerixafor

a b s t r a c t
Chemokines and their receptors organize the recruitment and positioning of cells at each stage of the
immune response, a system critically dependent upon coordination to get the right cells to the right
place at the right time. Chemokine receptors expressed on CLL B cells are thought to function in a similar
fashion, regulating the trafcking of the leukemia cells between blood, lymphoid organs, and the bone
marrow, and within sub compartments within these tissues, in concert with adhesion molecules and
other guidance cues. CLL cells not only respond to chemokines secreted in the microenvironment, the
leukemia cells also secrete chemokines in response to external signals, such as B cell receptor engagement.
These CLL cell-derived chemokines facilitate interactions between CLL cells, T cells, and other immune
cells that shape the CLL microenvironment. CXCR4, the most prominent chemokine receptor in CLL, is
now targeted in a rst clinical trial, emphasizing that chemokines and their receptors have become a
highly dynamic translational research eld.
2010 Elsevier Ltd. All rights reserved.

1. Chemokines and their receptors

The term chemokines initially was proposed in 1992 as a short
form of chemotactic cytokines, only a few years after discovery and characterization of the rst chemokine, interleukine-8
(IL-8) [1,2]. Subsequently, chemokines were characterized as a
family of cytokines that regulate cell trafcking and homing of
various immune cells. The human chemokine system currently
includes more than 40 chemokines and 18 chemokine receptors
[3]. Chemokines are small secreted proteins that are released either
constitutively or in response to stimulation, and cause migration of cells towards a gradient of the chemokine (chemotaxis).
Chemokines can be segregated into two main subfamilies based
upon whether or not two conserved cysteine residues present in all
chemokines are separated by an intervening amino acid, accounting for CXC or CC chemokines [3].
Chemokines bind to chemokine receptors, which belong to the
large family of seven transmembrane domain G-protein-coupled
cell surface receptors (GPCRs). Chemokine receptors are designated
CXCR1 through 5, CCR1 through 11, XCR1, and CX3CR1, based on
their specic preference for certain chemokines. Chemokines bind
to the extracellular domain of chemokine receptors, comprising
the N-terminus and three extracellular loops. Following activation, the intracellular domains (three loops and the C-terminus)

Tel.: +1 713 563 1487/792 1865; fax: +1 713 794 4297.

E-mail address: jaburger@mdanderson.org.
1044-579X/$ see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.semcancer.2010.09.005

cause dissociation of G-proteins, which are composed of three

distinct subunits (, , heterotrimers). This leads to formation
of the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG), resulting in cytoplasmatic calcium mobilization,
and activation of multiple downstream signaling cascades, such as
the phosphatidylinositol 3-kinase (PI3K)/Akt and the Ras/mitogenactivated protein-kinase (MAPK, also called ERK 1/2) signaling
pathways.
In the early 1990s, the function of chemokines as inammatory
mediators, causing trafcking and homing of inammatory cells to
sites of infection and inammation, was the main research area.
However, this rapidly changed after discovery of the co-receptor
function of the chemokine receptors CCR5 and CXCR4 for M- or Ttropic HIV-1 viruses in 1996 [4]. These discoveries ignited a broad
interest into studying the biology of chemokines in development,
immunity, and various diseases, and into developing drugs that
target chemokine receptors. Subsequently, T and B lymphocytes
were found to express receptors for various chemokines that are
constitutively expressed in tissue microenvironments, and their
expression and function is modulated during differentiation and
by lymphocyte activation [5]. These chemokine receptors allow
lymphocytes to respond to chemokines differentially expressed in
various tissue compartments and sub compartments [6,7].
Lymphocytes trafcking between blood and secondary lymphoid tissues, for example, is a non-random process that is
regulated by tissue-specic expression of chemokines [8]. Circulating blood lymphocytes interact transiently and reversibly
with vascular endothelium through adhesion molecules (selectins,

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425

integrins) in a process called rolling. Chemokines on the luminal

endothelial surface can activate chemokine receptors on the rolling
cells, which triggers integrin activation [9]. This results in the arrest,
rm adhesion, and transendothelial migration into tissues where
chemokine gradients direct localization and retention of the cells
[10]. These steps, collectively referred to as homing, are essential
for normal development of the organism, organization and function
of the immune system, and tissue replacement. There is a growing evidence that these physiologic mechanisms of tissue-specic
recruitment also are functional in neoplastic lymphocytes, such as
CLL cells.

2. Chemokine receptors on CLL cells

2.1. CXCR4
The CXCR4 chemokine receptor was among the rst chemokine
receptors characterized in CLL [11,12]. CXCR4 is expressed at high
levels on the surface of peripheral blood CLL cells [1114], and surface expression correlated with the clinical stage of the disease
in one study [15], but not in another one [14]. CXCR4 expression
is down regulated by its ligand CXCL12 (previously called stromal cell-derived factor-1/SDF-1) via receptor endocytosis [11]. This
characteristic can be used to distinguish tissue (lymphatic tissueand marrow-derived) from blood CLL cells, which express low or
high CXCR4 levels, respectively [11,15,16]. Proliferating, Ki-67+ CLL
cells isolated from marrow and lymphatic tissue displayed signicantly lower levels of CXCR4 and CXCR5 than non-proliferating CLL
cells [17]. Moreover, in vivo deuterium (2 H) labeling of CLL cells
revealed that patients with higher CXCR4 expression on their CLL
cells had delayed appearance of newly produced CD38+ cells in
the blood, and increased risk for lymphoid organ inltration and
poor outcome [18]. These 2 H studies also revealed intraclonal heterogeneity of CXCR4 expression, with an enrichment of CLL cells
expressing lower CXCR4 surface levels in the CD38+ /CD5bright fraction, along with increased 2 H incorporation [18]. These in vivo data
indicate that lower blood CXCR4 surface levels label a fraction of
CLL cells that has recently exited the tissues into the blood.
Functionally, CXCR4 mediates CLL cell chemotaxis, migration
across vascular endothelium, actin polymerization, and migration
beneath and underneath marrow stromal cells (MSC) that secrete
CXCL12 [11,19,20]. Besides its effects on CLL cell migration, CXCL12
also has a pro-survival effect on CLL cells, as demonstrated by using
recombinant CXCL12 and the nurselike cell (NLC) model in which
NLC constitutively secrete CXCL12 (Fig. 1) [2123]. This is not too
surprising, given that CXCL12 initially was characterized as a pre-B
cell growth factor and therefore initially was designated pre-Bcell growth-stimulating factor (PBSF) [24]. CLL cell responsiveness
to CXCL12 can be modulated by accessory signals from the CLL
microenvironment. B cell antigen receptor (BCR) signaling results
in down modulation of CXCR4 [25,26], along with enhanced chemotaxis towards CXCL12 and CXCL13, at least in our hands [25]. This
may explain why ZAP-70+ CLL cells display increased chemotaxis
and survival in response to CXCL12 when compared to ZAP-70negative CLL cells [23], given that ZAP-70 expression is associated
with a higher responsiveness to BCR stimulation [27]. CD38+ CLL
cell also display higher levels of chemotaxis [28], and CD38 activation with an agonistic monoclonal antibody (mAb) enhanced
chemotaxis towards CXCL12, whereas a blocking anti-CD38 mAbs
inhibited chemotaxis [29]. CXCR4 signaling in CLL cells is pertussis
toxin-sensitive and induces calcium mobilization, activation of PI3
kinases [11], p44/42 MAP kinases [21], and serine phosphorylation
of signal transducer and activator of transcription 3 (STAT3) [30].
Inhibition of CXCR4 signaling with isoform-selective PI3 kinase
inhibitors [31] or a Syk inhibitor [25] resulted in a reduction of

Fig. 1. Expression of CLL chemokine receptors, chemokines, and respective ligands. Accessory cells in the tissue microenvironments, collectively referred to as
stromal cells constitutively secrete the chemokines CXCL12, CXCL13, CCL19, and
CCL21. Through corresponding chemokine receptors expressed on the surface of the
CLL cells, the leukemia cells migrate and home to stromal cell niches in the tissue
compartments. As illustrated, chemokine receptors are 7-transmembrane receptors
coupled to cytoplasmatic G proteins which dissociate upon activation and cause
downstream signaling. Interferon-gamma induced chemokines (CXCL9, CXCL10,
CXCL11) bind to CXCR3, another CXC chemokine receptor expressed on CLL cells.
In response to B cell receptor (BCR) stimulation, CLL cells release the chemokines
CCL3 and CCL4, which, in turn can attract T cells and other immune cells. CCL3 and
CCL4 secretion by CLL cells can be blocked by inhibition of the spleen tyrosine kinase
Syk. CD40 ligation via CD40 ligand (CD154), expressed on activated T cells, induces
secretion of another chemokine, CCL22, which also can attract T cells for T cell-CLL
interactions.

chemotaxis and actin polymerization and reduced CLL cell migration beneath MSC.
Collectively, these data indicate that CXCR4 is involved in CLL
cell migration and homing to tissue niches, where stromal cellderived CXCL12 functions as a retention signal. Clinically, this
mechanism may be involved in drug resistance and minimal residual disease (MRD), given that CLL cells become highly resistant to
conventional cytotoxic drugs (udarabine, cyclophosphamide, and
dexamethasone) when cultured in the presence of MSC [30,32].
Conceivably, stromal cell niches in the marrow and lymphatic tissues may provide a sanctuary in which CLL cells are protected from
(immuno-) chemotherapy, accounting for MRD and relapses invariably seen after current CLL therapies [33]. CXCR4 can specically be
blocked by CXCR4 antagonists (reviewed in [34]), and we reported
that CXCR4 antagonists inhibit CLL cell activation by CXCL12, and
reverse, at least in parts, stromal cell-mediated drug resistance [30].
These data are the basis for an ongoing clinical trial in relapsed
CLL patients, in which patients are treated with the combination
of the anti-CD20 mAb rituximab and plerixafor, as small molecule
CXCR4 antagonist. Preliminary data from this trial indicate a plerixafor dose-dependent mobilization of CLL cells from the tissues to
the blood [35]. Other new targeted therapies in CLL, such as the Syk
inhibitor fostamatinib disodium [36], the Brutons tyrosine kinase
(Btk) inhibitor PCI-32765 [37], and the PI3K-delta inhibitor CAL101 [38] induce a transient lymphocytosis during the rst weeks
of treatment which presumably is due to mobilization of CLL cells
from the tissues into the blood. Inhibition of signaling through
CXCR4 and potentially other chemokine receptors and adhesion
molecules [25,31,39] seems to be the basis for this remarkable
phenomenon.

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J.A. Burger / Seminars in Cancer Biology 20 (2010) 424430

2.2. CXCR5
CXCR5 is the receptor for CXCL13, a homeostatic chemokine that
regulates lymphocyte homing and positioning within follicles of
secondary lymphoid tissues [40]. CXCR5 is expressed by mature
recirculating B cells, a small subset of CD4+ and CD8+ T cells, and
skin-derived migratory dendritic cells (reviewed in [41]). CXCR5
initially was isolated from Burkitts lymphoma and designated
Burkitts lymphoma receptor 1 (BLR1) [42]. CXCR5 gene deleted
mice display defective formation of primary follicles and germinal centers in the spleen and Payers patches, and lack inguinal
lymph nodes [43]. Subsequently, the ligand for CXCR5 was identied and termed B cell-attracting chemokine 1 (BCA-1) [44] and
now is designated CXCL13. CXCL13 is constitutively secreted by
stromal cells in B cell areas of secondary lymphoid tissues (follicles), where B cells encounter antigen and differentiate [8,40].
Generally, CXCR5 induces recruitment of circulating nave B cell
to follicles [8,40]. Regarding the microanatomic positioning within
the germinal center (GC), dark and light zones of GC can be distinguished, and centroblasts localize to the dark zones via CXCR4.
There, centroblasts rapidly divide and undergo somatic hypermutation of the antibody variable region genes. Subsequently,
they become smaller, nondividing centrocytes and migrate to light
zones of GC in a CXCR5-dependent fashion, where selection for
B cells with high afnity binding surface antibody occurs (afnity maturation) [4547]. A unique three-dimensional network of
CXCL13-expressing stromal cells provides the underlying roads
that B cells actively follow for localization within the follicles [48].
In addition to regulating lymphocyte migration and microarchitecture in secondary lymphoid tissues, the CXCR5CXCL13
axis appears to have a particularly important role in trafcking
of B1 B cells. B1 B cells are characterized and distinguished from
the majority of recirculating B cells (B2 cells) by their distinct
immunophenotype, tissue distribution, capacity for self-renewal,
and role in autoantibody production (reviewed in [49]). Initially,
B1 cells were described as a possible normal counterparts of CLL
B cells [50], characterized by the expression of high levels of surface IgM, low CD23 and surface IgD, and CD5 (B1a cells). B1 cells
are predominant in body cavities, but almost absent in secondary
lymphoid organs, and play a key role in production of nonspecic,
natural IgM antibodies for early protection from infections. B1 cells
display higher CXCR5 surface expression than B2 cells, and are
preferentially chemo-attracted to CXCL13 [51,52]. CXCL13 is also
produced by peritoneal macrophages, and B1 cell home to the peritoneal cavity in a CXCL13-dependent manner [52,53]. As such, it has
been suggested that the primordial function of CXCL13 may be the
recruitment of primitive B cells to body cavities for T-independent
responses, prior to its involvement in the complex lymphocyte
positioning during T-dependent antibody responses [52].
CLL cells express high levels of CXCR5 [13,20,5456]. CXCR5
expression levels were similar on CLL B cells and normal, CD5+ B
cells, and higher when compared to normal, CD5 negative B cells,
TFH cells, or neoplastic B cells from other B cell neoplasias [56].
Stimulation of CLL cells with CXCL13 induces actin polymerization,
CXCR5 endocytosis, chemotaxis [20], and prolonged activation of
p44/42 mitogen-activated protein kinases. In CLL, CXCR5 signals
through Gi proteins, PI3-kinases, and p44/42 MAPK pathway [56].
CXCL13 mRNA and protein is expressed by CD68+ NLC, in vitro and
in situ [56].
Because of its capability for inducing ectopic lymphoid-like tissues (lymphoid neogenesis) in chronic inammatory processes
and autoimmune diseases [57], it is tempting to speculate that
CXCL13 might also be involved in establishment and maintenance of the micro-architecture of lymphoid tissues inltrated by
CLL cells, characterized by proliferation centers (pseudofollicles).
Ectopic CXCL13 expression in the pancreas is sufcient to induce

lymphoid neogenesis [58], and CXCR5/CXCL13 has been implicated in ectopic lymphoid follicle formation in rheumatoid arthritis,
myasthenia gravis, other autoimmune and chronic inammatory
diseases. Aberrant B1 cell trafcking to CXCL13 plays a role in development of lupus in aged (NZB NZW)F1 (BWF1) mice. In these
mice, myeloid dendritic cells overexpress CXCL13 in the thymus,
kidneys, and spleen, inducing B1 cell recruitment to these target
organs [51]. Collectively, these data suggest that CXCR5 plays a role
in CLL cell positioning and cognate interactions between CLL and
CXCL13-secreting stromal cells, such as NLC in lymphoid tissues.
2.3. CXCR3
CXCR3 is the receptor for the CXC chemokines CXCL9, 10, and 11
(Table 1). These interferon-gamma (IFN)-induced chemokines are
mostly secreted at sites of inammation by various cells including
leukocytes, epithelial, endothelial, and stromal cells, and function
in a paracrine or autocrine fashion [59]. CXCR3 is expressed on
a subsets of normal B and T cells [60], and its expression can be
modulated by activation and differentiation [59]. CXCR3 is consistently expressed on CLL and splenic marginal zone lymphoma
B cells, but not on normal CD5+ B cells, and more inconsistently
on neoplastic B cells from patients with other B cell lymphomas
[54,61]. CXCR3 expression levels on CLL cells are variable, and low
CXCR3 expression was strongly associated with advanced stages
(Rai III/IV), diffuse marrow inltration, other risk factors, and poor
survival [62].
2.4. CCR7
CCL19 and CCL21 are ligands for the CCR7 receptor. CCL19 and
CCL21 are constitutively expressed by broblastic reticular cells,
high endothelial venules (HEVs), and dendritic cells (DCs) and play
a central role in lymph-node homing of nave and regulatory T cells
and DC [63]. Moreover the CCR7CCL19/CCL21 axis is involved in
organizing the architecture and function of the thymus. CCR7 is
expressed by DCs, thymocytes during dened stages of their development, nave B and T cells, regulatory and a subpopulation of
central memory T cells. CCR7 is also expressed by various neoplastic
cells, and CCR7 expression correlates with lymph node metastasis
in various solid tumors [64], including malignant melanoma, colorectal and prostate cancer. CCR7-decient mice develop changes
indicating autoimmunity, such as lymphocyte inltrates into
peripheral organs, increased titers of circulating auto-antibodies
leading to IgG deposition in renal glomeruli, and ectopic lymphoid
tissues in the lung, stomach and colon [63]. These changes could be
due to inefcient negative selection of autoreactive T cells in the
thymus, incomplete maintenance of peripheral tolerance or defective function of regulatory T cells [63]. Interestingly, CCR7 is also
involved in T and B cell recirculation. In sharp contrast to CXCR5decient mice, which show reduced peritoneal B-1 and B-2 B cells,
CCR7 deciency results in a massive accumulation of T cells and B-2
B cells in the peritoneal and pleural cavities, caused by an impaired
egress of CCR7-decient lymphocytes from body cavities [65].
CLL cells express CCR7 and migrate across vascular endothelium in response to CCL19 and CCL21 [19,55]. Moreover, expression
levels of CCR7 correlated with lymphadenopathy [19,55] and
expression of ZAP-70 and CD38 [23]. CCL19- and CCL21-induced
migration and actin polymerization of ZAP-70+ /CD38+ CLL cells was
higher when compared to CLL cells lacking ZAP-70 and CD38 [23].
Moreover, CCL21 signicantly increased B-CLL metalloproteinase9 (MMP-9) production in MAP kinase- (ERK1/2-) dependent fashion
[66], suggesting cross talk between these pathways during trafcking and tissue homing. CCR7 signaling for chemotaxis in response to
CCL19 and CCL21 involves PI3 kinases and the Rho kinase [67]. AntiCCR7 mAbs recently were shown to cause complement-dependent

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427

Table 1
Chemokine receptors expressed by CLL cells.
Receptor

Other names

Ligands

Expression in CLL

Presumed functions

CXCR3

CD182, GPR9

CXCL9, CXCL10, CXCL11

Low/intermediate, consistently
expressed [54,61]

CXCR4

CD184, Fusin, HM89, LCR1,

LESTR

CXCL12

CXCR5

CD185, BLR1, MDR15

CXCL13

High [11,12], downregulated by

CXCL12 (receptor endocytosis) [11]
and by BCR triggering [25]
High [56]

Th1 response, angiostasis, leukocyte

recruitment, inammation, integrin activation,
cytoskeletal changes, and chemotactic
migration
Organogenesis, lymphopoiesis, hematopoiesis,
cell migration and survival, angiogenesis

CCR7

CD197

CCL19, CCL21

Intermediate to high, correlates

with lymphadenopathy [19,55]

B-cell migration, Th2 response, organogenesis

(cooperative with the CCR7 receptor)
T cell development in the thymus, lymph-node
homing of nave and regulatory T cells and
dendritic cells

Table 2
Inducible chemokines expressed by activated CLL cells.
Chemokine

Other names

Receptor

Expression in CLL

Presumed functions

CCL3

MIP-1; SCYA3; G0S19-1; LD78ALPHA

CCR1 and CCR5

After BCR-triggering and NLC

co-culture [79], higher in ZAP-70+
CLL, Syk-dependent [25]

CCL4
CCL22

MIP-1, SCYA4
DC/B-CK, MDC, MDC (169), MGC34554,
SCYA22

CCR5
CCR4

Same as for CCL3

After CD40 ligation

Inammation, recruitment and

activation of polymorphonuclear
leukocytes, activated B cells:
recruitment of T cells for T-B cell
interactions
Same as for CCL3
Recruitment of regulatory T cells (Treg )

cytotoxicity against CLL cells and therefore were proposed as a

potential therapeutic agent [68]. Overall, these data support the
concept that CCR7 plays an important role in trafcking and homing
of CLL cells to the lymphatic tissues.
3. Chemokines secreted by CLL cells
3.1. CCL3 and CCL4
CCL3 and CCL4, previously called Macrophage Inammatory
Proteins-1 alpha and beta (MIP-1,) are chemokines of the
CC subfamily and inducible in a number of hematopoietic cells,
particularly in those involved in adaptive immune responses
(macrophages, dendritic cells, and B and T lymphocytes). CCL3 signals through the chemokine receptors CCR1 and CCR5, whereas
CCL4 signals only through CCR5. CCL3 and CCL4 are chemoattractants for monocytes and lymphocytes [69]. CCL3 expression in B
cells is induced by BCR triggering and CD40 ligand [7072], and
repressed by Bcl-6 [73].
There is growing evidence that CCL3/4 also plays an important
role in B cell malignancies. Gene expression proling revealed that
expression of SCYA3, the gene encoding for CCL3, is part of the activated B-cell (ABC) signature [74,75] and predicts for poor survival
in patients with diffuse large B-cell lymphoma (DLBCL) [76]. In multiple myeloma, CCL3 expression by the malignant B cells correlated
with lytic bone lesions and poor survival [77,78].
Previous studies demonstrated CCL3/4 overexpression and
secretion by activated CLL cells [7981] and elevated CCL3/4 plasma
levels in CLL patients [79,82]. We reported that CLL cells upregulate
and secreted CCL3/4 in response to BCR stimulation and in coculture with nurselike cells (NLCs) [79], a model system resembling
the lymphatic tissue microenvironment [21,22,83,84]. This BCRand NLC-dependent induction of CCL3/4 was sensitive to inhibition of BCR-signaling, using a spleen tyrosine kinase (Syk) inhibitor
[25,79]. The function of CCL3/4 in CLL remains poorly dened, but
based upon the function of B cell-derived CCL3/4 in normal immune
responses, we hypothesized that increased CCL3/4 secretion by CLL
cells may induce trafcking and homing of accessory cells, particularly of T cells, to CLL cells in the tissue microenvironments [79].

This is supported by in vitro [70,85] and in vivo [86,87] studies which

indicated that CCL3/4 display a specic function in the lymphatic
tissues. These studies demonstrated that B cell activation within
lymphoid tissues results in CCL3/4 secretion, leading to the recruitment of CCR5+ regulatory T cell for cognate interactions with B cells
and antigen presenting cells [86,87]. It is also well recognized that
CLL cells in the proliferative compartment are interspersed with T
cells [88,89] and NLC [56,90,91]. Conceivably, by attracting T cells
and other immune cells for cognate interactions with the leukemia
cells, CLL cell-derived CCL3/4 (and CCL22, see below) actively foster
the co-evolution of CLL cells and their supportive microenvironment, actively creating a favorable microenvironment in which CLL
cells interact with T cells and other accessory cells that deliver
survival- and proliferation-signals.
3.2. CCL22
Regulatory T cells (Treg ), identied by expression of the transcription factor FoxP3, typically express the chemokine receptor
CCR4 and migrate towards the ligands for CCR4, called CCL22 and
CCL17. It was proposed that CCL17 and/or CCL22 secretion could
be responsible for an accumulation of FoxP3+ Treg cells in the in
the tumor microenvironment, which might suppress local immune
responses and favor tumor progression in diseases such as breast
cancer or Hodgkins disease [92,93]. CLL cells obtained from the tissues, but not from the blood express CCL22 and variable levels of
CCL17 mRNA. After CD40 ligation, CCL22 and CCL17 mRNA became
induced in blood CLL cells, and CCL22 protein was released into CLL
cell supernatants, which in turn attracted CCR4+ T cells. Besides
CCL3/4, CCL22 therefore may function as another CLL cell-derived
chemoattractant which could recruit T cells and potentially other
immune cells for interactions with CLL cells in the tissue microenvironment (Table 2).
3.3. IL-8
Interleukine-8 (IL-8) is a member of the CXC chemokine family and plays an important role in autoimmune, inammatory, and
infectious diseases. CLL cells have been reported to secrete IL-8 in

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J.A. Burger / Seminars in Cancer Biology 20 (2010) 424430

response to CD40 [94] or CD74 stimulation, which may regulate

CLL survival and/or interactions with the microenvironment [95].
Elevated plasma IL-8 levels correlated with other prognostic factors and clinical outcome [96], suggesting that this chemokine may
have a relevant role in vivo.
4. Therapeutic targeting of chemokines and their receptors
in CLL
4.1. The CXCR4CXCL12 axis
CXCL12 is constitutively secreted by marrow stromal cells
(MSC), and induces leukemia cell trafcking and homing to the
marrow microenvironment in vitro [11] and in vivo [97] via CXCR4
receptors, which are expressed at high levels on circulating CLL
cells. In the marrow microenvironment, CXCL12 retains leukemia
cells in MSC niches that provide growth and drug-resistance signals. CXCR4 antagonists, such as plerixafor (AMD3100) and T140
analogs, can disrupt adhesive CLLstroma interactions [30] and
mobilize CLL cells from their protective tissue microenvironments
to the blood, making them more accessible to conventional drugs.
Therefore, targeting the CXCR4CXCL12 axis is a novel, attractive
therapeutic approach that is currently explored in a rst clinical
trial in CLL patients [35]. Initially, CXCR4 antagonists were developed for treatment of HIV, where CXCR4 functions as a co-receptor
for virus entry into T cells. Subsequently, CXCR4 antagonists were
noticed to induce leukocytosis, and currently are used clinically for
mobilization of hematopoietic progenitors in the context of autologous stem cell mobilization in myeloma and lymphoma patients.
The ongoing CLL trial combines plerixafor with rituximab, and the
rst preliminary data indicate a plerixafor dose-dependent CLL cell
mobilization to the blood, as well as safety of this drug combination [35]. Future studies in CLL using this approach of leukemia
cell mobilization and sensitization could combine a CXCR4 antagonist with established CLL drugs, such as antibodies (for example
rituximab, alemtuzumab, lumiliximab, ofatumumab), or combine
a CXCR4 antagonist with established cytotoxic agents such as
udarabine, bendamustine, cyclophosphamide, or combinations
of antibodies and cytotoxic agents (chemo-immunotherapy). An
alternative approach would be the use of a CXCR4 antagonist in the
setting of residual disease (MRD), where these agents could help to
mobilize and then eliminate residual CLL cells from tissue sites.
A large number of chemokine and chemokine receptor
antagonists are currently under development, mostly in autoimmune/inammatory diseases (reviewed in [98]). These developments, along with the promising data from the ongoing CXCR4
antagonist trial in CLL [35] indicate that chemokine receptors are
becoming valid therapeutic targets, which may lead to new therapeutic avenues for patients with CLL.
Conict of interest
Jan A. Burger is a consultant for Genzyme, Cellgene, Pharmacyclics.
Acknowledgements
This work was supported by a CLL Global Research Foundation
grant and an ASCO Career Development Award (to J.A.B.).
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