The Biology of Hairy Cell Leukemia 9
originate from the still unknown oncogenic event(s) are frequently constitutively activated and interact
causing the disease. with their ligands without further stimulation. As will
be discussed later these receptors and their ligands
determine the tissue interactions of HCs.
Hairy cells as possible memory cells
DNA microarray analysis of the expression of a very
Activated signaling components
large number of genes has shown that HCL clones
display a homogenous phenotype distinct from that As again might be expected, a number of signaling
of other B-cell malignancies [2]. This is to be components have now been shown to be activated in
expected since it has long been recognized that HCs. These activated signals and their functional
HCL, unlike CLL for example, is a rather homo- relevance are summarized in Table III.
genous entity both clinically and pathologically.
More interestingly, this DNA microarray analysis
The susceptibility of hairy cells to interferon and
also showed that HCs resemble memory B cells more
nucleosides (e.g. deoxycoformycin, chlorodeoxyadenosine,
than any of the other B-cell types examined. Never-
and fludarabine)
theless, HCs lack CD27 protein, a specific marker of
normal memory B cells. All in all, therefore, there is Among the hemic malignancies, HCL is unusually
still some doubt about the precise nature of HCs and sensitive to these agents. The sensitivity of HCs to
their normal counterpart, but they may be related to interferon has been studied in some detail and has
splenic marginal zone cells with memory character- been shown to be a result of the effects of the
istics [4]. cytokine on TNF/NFkB signaling [5]. Although
much is known about the effects of nucleosides on
lymphocytes, it remains unclear why HCs are so
Cytokine production
sensitive to the killing effects of these agents.
As might be expected from their activated phenotype,
HCs produce a number of pathogenetically relevant
Cytogenetics and oncogenic event(s)
cytokines and cytokine receptors. These are sum-
marized in Table I and the cytokines can have both HCs contain no consistent or specific cytogenetic
autocrine and paracrine effects. HCs also express abnormalities. Thus, cytogenetic studies have not
receptors for IL-2 (CD25) and IL-3 (CD123); both provided any firm clues concerning possible onco-
receptors have diagnostic significance, but no func- genic stimuli in HCL and the transforming events
tional effects of either cytokine have been demon- causing the disease remain unknown.
strated.
Interaction of hairy cells with the microenvironment
Adhesion and homing
The principal clinico-pathological features of HCL
HCs express a distinctive pattern of adhesion/homing are listed in Table IV. These result from the
receptors, which are summarized in Table II. These accumulation of HCs in the spleen, the bone marrow
Table I. HC cytokines and their receptors.
Cytokine Receptors on HCs Comment
TNF-a TNFRI and RII present Involved in HC survival and response to IFN therapy.
IL-6 Present Production may be induced by TNF. May participate in the proliferative
effects of TNF.
IL-10 Not studied Suppresses TH1 cytokine production.
GM-CSF Receptor present Prolongs the survival of HCs and inhibits their motility.
M-CSF Receptor present Stimulates chemokinesis and chemotaxis of HCs.
FGF Both FGFR1 and CD44v3 Involved in FN production by HA-adherent HCs.
co-receptor present
TGFb Not studied Elevated in HCL serum and BM. May be involved in the suppression of
the production and function of normal hematological cells.
IFNa Receptor present Induces HC apoptosis in the absence of cell adhesion and may induce
autocrine production of TNF.
HC, hairy cells; TNF-a, tumor necrosis factor-a; IFN, interferon; IL-6, interleukin-6; IL-10, interleukin-10; GM-CSF, granulocyte-
macrophage colony-stimulating factor; M-CSF, macrophage colony-stimulating factor; FGF, fibroblast growth factor; TGFb, transforming
growth factor beta; INFa, interferon alpha.
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