Survival Cytokines

CLL is an accumulative disorder, characterized by low proliferative activity and by the progressive accumulation of clonal B-lymphocytes blocked in the early phases (G0/G1) of the cell cycle (1). In the pathogenesis of the disease an important role is thus played by the dysregulation of cellular mechanisms that control the progression through the cell cycle and the activation of programmed cell death (2). Abnormal cytokine loops may favor the survival and expansion of the leukemic clone through induction of cell proliferation or protection from apoptosis. In fact, defective apoptosis is considered to play a major role in the pathogenesis of the disease, and most cytokines capable of sustaining the leukemic cell growth act by inhibiting programmed cell death. Also, the cellular mechanisms that mediate these effects are shared by different cytokine networks that in many cases are thought to involve the regulation of the anti-apoptotic gene bcl-2, as will be discussed below in Subheadings 2.3., 2.5., and 2.8. Furthermore, many of these cytokines are members of the cytokine receptor family, which utilizes a common family of signal transduction molecules; the Janus kinase (JAK) kinases and signal transducer and activation of transcripton (STAT) signal transduction molecules (3). In CLL patients, several cytokines are secreted by the non-neoplastic accessory cell compartment, and the in vivo survival advantage is induced by

From: Contemporary Hematology Chronic Lymphocytic Leukemia: Molecular Genetics, Biology, Diagnosis, and Management Edited by: G. B. Faguet © Humana Press Inc., Totowa, NJ 123

Table 1

Cytokines in CLL

Table 1

Cytokines in CLL

Cytokine

Activities

Survival cytokines

IL-1p '

Inhibits apoptosis

IL-2

Costimulates proliferation

IL-4

Inhibits or increases proliferation

Protects from apoptosis

IL-6

Protects from apoptosis

IL-8

Inhibits apoptosis

IL-10

Contrasting data: may induce or prevent apoptosis

TNF-a

Contrasting data: may increase or inhibit proliferation

May suppress apoptosis

IFN-a/y

Inhibits apoptosis

G-CSF/GM-CSF

Decrease apoptosis

Inhibitory cytokines

IL-5

Induces apoptosis

TGF-p

Inhibits proliferation

GM-CSF, granulocyte/macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor; TGF, transforming growth factor.

GM-CSF, granulocyte/macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor; TGF, transforming growth factor.

increased serum levels or by the peculiar response of the leukemic cells; there is, however, growing evidence that CLL cells themselves are capable of producing many autocrine factors that enhance their life span.

Finally, as in many hematological malignancies, a relevant role in disease control could be played by the antitumor immunological response. A permissive role may then be played by dysregulated cytokine pathways that could influence the function of the residual non-neoplastic immune system.

Below, we will individually discuss some of the cytokines and soluble molecules that have gained more attention, and their possible involvement in CLL. A short summary of potential activities of different cytokines in B-CLL is reported in Table 1.

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