10 J. Cawley
(BM), and the liver where they alter the microenvir- normal hematopoiesis. The pathophysiology of the
onment in distinctive ways. distinctive BM fibrosis of HCL has been studied in
some detail [6]. Interaction of HCs with the tissue
matrix component, hyaluronan (HA), is key to the
Spleen
process. This interaction stimulates the HCs to make
HCs accumulate in the red pulp of the spleen and fibroblast growth factors (FGF) which then stimu-
obliterate the white pulp. The HCs then form the lates the malignant cells to synthesize and secrete the
so-called pseudosinuses by replacing the endothelial fibronectin (FN), a major component of the BM
cells of the red pulp to form these widened vascular matrix in HCL. The HCs then interact with the
channels. This causes the pooling of red cells in the FN via their activated integrin receptors. This
spleen – a process that contributes to the anemia of process results in the distinctive BM fibrosis of the
the disease. disease.
Bone marrow Liver
Here, the HCs alter the microenvironment by Here, the HCs infiltrate both the hepatic sinu-
producing extensive fibrosis and by suppressing soids and the portal tracts. In the sinusoids, they
Table II. HC adhesion receptors.
Integrins (CD) Possible functions
Adhesion receptors
a
4
b
1
(49d/29) Involved in binding to matrix (FN) and accessory cells via CD106 (VCAM)
a
5
b
1
(49e/29) Involved, together with a
4
b
1
in binding to, and assembly of, FN matrix
a
M
b
2
(11b/18) Weakly expressed. Constitutes a monocytic feature of HCs and may be involved in endocytosis
a
X
b
2
(11c/18) Diagnostically important. Receptor for a number of ligands, including ICAM-1 (CD54), but function in
HCs unclear
a
V
b
3
(51/61) Receptor for vitronectin (VN) and PECAM-1 (CD31). Important in HC motility
a
E
b
7
(103/b
7
) Diagnostically important. Receptor for E cadherin, but function in HCL unclear
Other adhesion receptors
CD44 Highly expressed. HC receptor for hyaluronan.
Several isoforms expressed (V3, V6)
CD44H signals for FGF production;
V3 (heparin sulphate-containing isoform) acts as a co-receptor with FGFR-1 for stimulation of HC FN
production by FGF
L-selectin (62L) Little or no expression. Shed on cell activation
HC, hairy cells; FN, fibronectin; VN, vitronectin; VCAM, vascular cell adhesion molecule.
Table III. Activation signals in HCs.
Signal Possible origin Functional relevance
Elevated intracellular [Ca
2þ
] Release from intracellular stores in response Activation messenger
to autocrine cytokine.
Influx via highly expressed and
phosphorylated CD20
Increased protein tyrosine Constitutively activated Src Downstream activation of Rho GTPases, PKCs, and
phosphorylation MAP kinases
Active Rac and Cdc42 Src-activated GEF(s) Formation of surface ruffles and microvilli and
downstream activation of MAP kinases
Activated PKCs Upstream activators include high [Ca
2þ
], Regulation of MAP kinases and NFkB involved in
PLC-generated DAG, and Src cell survival and proliferation
Activated MAP kinases ERK activation constitutive and PKC dependent. ERK provides a pro-survival signal
P38 and JNK induced by external signals P38 is pro-apoptotic
(e.g. TNF) and suppressed by activate PKCa JNK stimulates CD11c expression via AP-1 complex
formation
Activated NFkB Autocrine TNF and integrin signaling Stimulates IAP production.
Suppression of IAPs involved in the aIFN-induced
sensitivity of HCs to TNF killing
PKC, protein kinase C; GEF, guanine nucleotide exchange factor; IAP, inhibitor of apoptosis protein.
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46