Activated Signalling Components

A number of signaling components are now known to be activated in HCs. The so-far identified activation signals and their likely mutual relationships are summarized in Table 29.4. Some of these signals are transient and clearly originate from cell stimulation by components of the in vivo microenvironment, but some persist in vitro, suggesting that they are truly constitutive. It is, however, not yet clear which of these constitutive signals is a direct consequence of the still unknown oncogenic event(s), and which are attributable to autocrine cytokine production. The pathogenetic role

Table 29.4 Activation signals in HCs


Possible origin

Functional relevance

Elevated intracellular [Ca2+]

Release from intracellular stores in response to autocrine cytokine.

Influx via highly expressed and phosphorylated CD20

Activation messenger

Increased protein tyrosine phosphorylation

Constitutively activated Src

Downsteam activation of Rho GTPases, PKCs and 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 [Ca2+],PLC-generated DAG and Src

Rgulation of MAP kinases and NFkB involved in cell survival and proliferation

Activated MAP kinases

ERK activation constitutive and PKC dependent p38 and JNK induced by external signals (e.g., TNF) and suppressed by active PKCa

ERK provides a pro-survival signal p38 is pro-apoptotic JNK stimulates CD11c expression via AP-1 complex formation

Activated NFkB

Autocrine TNF and integrin signaling

Stimulates IAP production. Suppression of lAPs involved in the alFN-induced sensitivity of HCs to TNF killing

of these signals will be considered in the section dealing with the pathology of the disease.

The first demonstration of a messenger that could be responsible for the activated state of HCs was provided by Genot et al., who showed elevated [Ca2+] in HCs and identified phosphorylated CD20 as an influx channel involved in this Ca2+ elevation.89 Ca2+ / calmodulin-dependent protein kinase II may be responsible for the CD20 phosphorylation and for the maintenance of Ca2+ influx.9 Interestingly, HC treatment with a interferon reduced CD20 phosphorylation and the cytosolic Ca2+ level,10 and the authors suggested that this might be a part of the mechanism of the therapeutic action of this agent in HCL.

Increased expression of Src and high protein tyro-sine kinase activity in HCs have also been recognized for some time.11 More recently, it was demonstrated that Src-dependent tyrosine phosphorylation is responsible for downstream activation of many other signaling components, including Rho GTPases,12 PKCs, and MAP kinases.13 Rac and Cdc42, the two constitutively active Rho GTPases in HCs, are responsible for the distinctive morphological features of these malignant cells,12 as well as for their adhesive and motile behavior on different substrates.14 In addition to regulating cytoskeletal dynamics, Rac and Cdc42 are also likely to be involved in the activation of MAPKs.15

PKC(s) involvement in activation of HCs has long been suspected, as other B cells treated with phorbol esters acquire HC-like morphology and TRAP expression. More recent work has revealed the presence in HCs of at least six PKC isoforms, of which only PKCa was consistently found to be strongly constitutively active.13 Furthermore, PKCs were found to be crucially involved in the regulation of MAPKs in HCs. Thus, HC incubation with PKC inhibitors caused a rapid fourfold increase in p38 MAP kinase activation and an equally rapid downregulation of constitutive ERK activity.13 This was followed by pronounced shortening of cell survival, a finding in accordance with the proposed central role of the balance between activations of cytoprotective ERK and pro-apoptotic p38/ JNK in the regulation of cell survival.16

HCs produce large amount of TNF and possess both TNFR1 and TNFR2.17'18 Autocrine TNFa increases cell survival,19 but in the presence of aIFN this pro-survival effect is converted to a pro-apoptotic one.20 This cell killing is brought about by IFN-induced suppression of IAP (inhibitors of apoptosis) production regulated by the NFKB-dependent arm of TNF signaling. HC adhesion to vitronectin and fibronectin stimulates IAP production that is not inhibited by aIFN, and can therefore provide relative protection of HCs from this IFN-induced, TNF-mediated killing.20

Thus, intrinsic activation of malignant HCs is highly relevant for both pathogenesis and therapy of HCL. Therefore, studies of the signaling pathways involved may suggest new therapies, and may give some insight into the elusive nature of the primary oncogenic event(s) responsible for the intrinsic activation and developmental arrest of HCs.

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