Elsevier

Leukemia Research

Volume 37, Issue 7, July 2013, Pages 838-847
Leukemia Research

Invited review
The biological rationale and clinical efficacy of inhibition of signaling kinases in chronic lymphocytic leukemia

https://doi.org/10.1016/j.leukres.2013.03.011Get rights and content

Abstract

Chronic lymphocytic leukemia (CLL) is still incurable, with considerable resistance to the standard therapy. CLL cells receive anti-apoptotic and pro-proliferation stimuli in lymph nodes and bone marrow, mainly through B cell receptor activation and TNF-receptor family ligation. In recent years, the focus for finding new drugs has shifted to blocking signals from the microenvironment. Novel therapeutical agents interfere with these microenvironmental interactions, and include inhibitors of kinases Syk, Btk and PI3Kδ. In this review we will focus on the microenvironmental interactions of CLL and the role of tyrosine kinases. Furthermore, early results from clinical trials with kinase inhibitors are discussed.

Introduction

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B lymphocytes accumulating in the peripheral blood (PB), lymph nodes (LN), bone marrow (BM), spleen and liver [1]. CLL mainly affects the elderly and has a highly variable course. Standard therapy for fit patients has shifted from monotherapy with alkylating agents aiming at alleviation of symptoms to immunochemotherapy with the goal of prolonged progression free survival and improved overall survival [2]. Still, such treatments are not considered curative.

In recent years it has become evident that for survival and proliferation CLL cells are highly dependent on external stimuli. Only very recently, these interactions became the focus of novel treatment options, which will likely radically change the outcome of this disease.

Despite their malignant nature CLL cells retain their susceptibility to external signals in LNs and BM, largely resembling mature healthy B cells. These interactions are collectively referred to as the microenvironment. Healthy B cells become activated upon antigen ligation to the B cell receptor (BCR), resulting in proliferation and differentiation. This can be further enhanced by cytokine stimulation and co-stimulation. The various signals from the microenvironment together orchestrate the activation of B cells and likewise of CLL cells. The LNs and BM thus provide a protective niche for CLL cells, enabling progression of the disease [3].

Kinases play a key role within the signaling cascades activated upon microenvironmental interactions. Several new therapeutic strategies that are currently under investigation for CLL specifically aim to inhibit kinases. Understanding the role of signaling kinases is mandatory for designing novel trials which aim to target the microenvironment. We will first review the current vision of the dominant external stimuli present in the CLL microenvironment. We then summarize evidence for activation of key signaling cascades in CLL. Finally, we will discuss the first clinical results of kinase inhibitors in CLL.

Section snippets

Key factors that enhance activation of CLL cells

A large number of factors have been studied that may contribute to the activation of CLL cells. Factors that potentially contribute include cell–cell contact, chemokines, cytokines and activation of the BCR [4], [5]. While many of these factors appear to contribute in vitro, it is yet to be defined which factors are relevant for CLL cell activation in vivo. A comparative study of expression levels of apoptotic regulators in CLL cells residing in the PB versus LNs revealed overexpression of

Ligation of TNF-receptor family members

TNF receptor family members are key players in regulating immune functions. Upon activation of TNF receptors, proliferation, apoptosis and differentiation of immune cells may be modified. The ligands for TNF receptors present in the microenvironment of CLL cells include among others CD40L, BAFF and APRIL [18].

Upstream signaling events

Stimuli from the microenvironment trigger specific signaling cascades in CLL cells, which bear extensive resemblance to signaling cascades of healthy B cells. To provide a better understanding of the pathogenesis of CLL, a summary of upstream signaling cascades concerning the BCR and TNFRs in healthy B cells will shortly be described. While the B cell receives numerous stimuli, including cytokines and chemokines, only signaling cascades that involve the BCR and TNFRs will be discussed here, for

Kinase inhibitors in CLL

Inhibition of key signaling kinases aims at depriving CLL cells of microenvironmental stimuli. In vitro experiments suggest that inhibition of signaling pathways not only deprives CLL of these stimuli, but may also lead to direct apoptosis [50], [60]. Currently, the broad-spectrum kinase inhibitor dasatinib as well as selective kinase inhibitors of Syk, Btk and PI3Kδ have been studied clinically in CLL. The first results with kinase inhibitors are summarized in Table 2 (monotherapy) and Table 3

Conclusion

Selective kinase inhibitors have recently entered the clinic, showing very promising results. Knowledge on signaling cascades and the precise role of the targeted kinases in leukemias and lymphomas is still incomplete. An important mode of action is the inhibition of microenvironmental interactions. Kinase inhibitors disrupt adhesion and migration of CLL cells in the LNs and BM, resulting in a shift toward the PB. Cells are more prone to spontaneous and drug-induced apoptosis in the PB. Besides

Conflicts of interest statement

The authors declare no conflict of interest.

Acknowledgements

APK is sponsored by a fellowship from the Dutch Cancer Society.

Contributions: IdW and APK wrote the manuscript. EE and MHvO reviewed the manuscript.

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