H e m a t o lo g y E d u c a t io n - European Hematology Association

Regulatory T cells (T reg), identified 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 + T reg cells in
the in the tumor microenvironment, which might suppress
local immune responses and favor tumor progression
in diseases, such as breast cancer or Hodgkin’s disease.
86,87 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. Conceivably, by attracting
T cells and other immune cells, CLL cell-derived
chemokines 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.
VLA-4 (CD49d) adhesion molecules in CLL
Integrins are a superfamily of heterodimeric glycoproteins,
consisting of various a (1 through 11) and b
(1 through 6) subunits, whose function is to mediate
cell-cell and cell-matrix adhesion in various cell types.
The term “integrin” was first proposed in 1986 to
describe membrane complexes involved in the transmembrane
association between fibronectin as part of
the extracellular matrix (ECM) and the actin cytoskeleton.
88 Integrins are categorized into subfamilies with
members sharing a common b subunit pairing with a
unique a subunit. b 1 integrins are very late activation
antigens (VLA) that have the same b 1 subunit but various
a chains (a 1 through 6). 89 The a 4b 1 integrin VLA-
4 (CD49d) is a receptor for fibronectin (FN) and vascular
cell adhesion molecule-1 (VCAM-1/CD106, Figure
2). VLA-4 is expressed on lymphocytes, monocytes,
and most other hematopoietic cells (except for neutrophils);
VLA-4 is involved in both cell-cell and cellextracellular
matrix adhesion and plays a role in lymphocyte
trafficking and homing as part of immune surveillance,
32 trafficking, and homing of other
hematopoietic cells, and inflammation. Integrins are
highly versatile adhesion molecules; their adhesiveness
can rapidly be regulated by the cells on which
they are expressed, for example, by chemokine receptor
activation. 26 VLA-4 mediates lymphocyte adhesion
to the VCAM1, also known as CD106, which is
expressed on cytokine-activated endothelium.
VCAM1 mediates leukocyte-endothelial cell adhesion,
and may play a role in the development of artherosclerosis
and rheumatoid arthritis. VLA-4 also binds
fibronectin, an ECM component expressed on MSC, 90
by interacting with at least three fibronectin sites, CS-
1 and REDV in the IIICS region, and H1 in the HepII
region. 91 VLA-4 plays a particularly important role for
interactions between normal and malignant
hematopoietic cells and the marrow microenvironment.
Ryan et al. 92 and Dittel et al. 93 demonstrated that
VLA-4 and VCAM-I are involved in the adhesion of
human B cell precursors to MSC. Matsunaga and colleagues
demonstrated that VLA-4 mediates drug resist-
London, United Kingdom, June 9-12, 2011
ance, and anti-VLA-4 mAbs induce long-term diseasefree
survival in a mouse model of acute myelogenous
leukemia (AML). 90 VLA-4 integrins cooperate with
chemokine receptors in CLL cell adhesion to stromal
cells. 11,94 Moreover, VLA-4 expression on CLL cells has
prognostic impact, 95,96 indicating the relevance of these
interactions in vivo. Collectively, these studies indicate
that VLA-4 integrins play a key role for adhesion of
CLL and other leukemia cells to stromal cells and
ECM, and provide a rationale to further explore and
target this molecule in CLL.
Figure 2. Molecular interactions in the CLL microenvironment.
This diagram depicts molecular interactions
between CLL and stromal cells in the marrow and/or lymphoid
tissue microenvironments that are considered
important for a) CLL cell survival and proliferation (left
hand side) or b) CLL cell homing and retention in the tissues
(right hand side, adapted after 16 ). Contact between
CLL cells and NLC or MSC is established and maintained
by chemokine receptors and adhesion molecules
expressed on CLL cells. NLCs express the chemokines
CXCL12 and CXCL13, whereas MSCs predominantly
express CXCL12. NLCs and MSCs attract CLL cells via the
G protein-coupled chemokine receptors CXCR4 and
CXCR5, which are expressed at high levels on CLL cells.
Integrins, particularly VLA-4 integrins (CD49d), expressed
on the surface of CLL cells cooperate with chemokine
receptors in establishing cell-cell adhesion through respective
ligands on the stromal cells (VCAM-1 and
fibronectin/FN). The precise role of Syk, Btk, and PI3 kinases
(PI3Ks) for signaling of chemokine receptors and adhesion
molecules in CLL is defined in ongoing studies.
However, the clinical responses to small molecule antagonists
to each of these kinases indicate an important role
of these kinases for CLL tissue homing and retention, likely
involving chemokine receptor- and integrin-signaling, as
indicated in the diagram.
Self and/or environmental antigens (Ag) are considered a
key factor in activation and expansion of the CLL clone.
The nature and source of Ag and its mode of presentation
to CLL cells are largely unknown and currently the focus of
intensive research. Stimulation of the BCR complex (BCR
and CD79a,b) induces downstream signaling by recruitment
and activation of Syk, Btk, and PI3Ks. Finally, BCR
stimulation and co-culture with NLCs also induce CLL cells
to secrete high levels of chemokines (CCL3, CCL4) which
are potent T cell–attracting chemokines. Through this
mechanism, CLL cells can actively recruit T cells for cognate
T-cell interactions with CLL cells. CD40L + T cells are
preferentially found in CLL proliferation centers 18 and can
interact with CLL cells via CD40.
Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 95 |