B-cell receptor signaling in chronic lymphocytic leukemia leans on Lyn

B-cell receptor (BCR) signaling is essential for normal B-cell selection, differentiation, survival, proliferation and antibody formation. The BCR transmits two types of signals, one of which is antigen-independent (“tonic”) and the other antigen-dependent. As in normal B-cells, BCR signaling also plays a crucial role in the pathogenesis of chronic lymphocytic leukemia (CLL), and support for this is provided from data relating to gene expression and the immune-phenotype of CLL cells as well as their BCR structure, the patterns of antigen recognition and downstream signaling pathways, and their association with clinical outcome [1–8]. In this regard, the gene expression profile and phenotype of CLL cells resemble activated/memory B-lymphocytes, presumed to derive from antigen experienced B-cells [1–3]. Two main subtypes of CLL are basically defined by the somatic hypermutation status of the immunoglobulin heavy chain variable region (IGVH) [4,5]. Patients with a mutated IGVH gene clone have a more favorable clinical course and outcome than those with unmutated or germ-line immunoglobulin [4,5]. Generally in CLL, the BCR in leukemic cells with unmutated IGVH is competent and responds more readily to stimulation, while those cells with mutated IGVH are typically unresponsive, suggestive of anergized B-cells which have been exposed to chronic antigen stimulation [9,10].

The differences in the BCR responsiveness in CLL have also been attributed to aberrant expression of zeta-associated protein of 70 kDa (ZAP-70), a tyrosine protein kinase which is normally involved in the downstream signaling of the T-cell receptor [6,7]. ZAP-70 is commonly expressed in IGVH unmutated CLL cells but is usually absent in cells with mutated IGVH. The presence of ZAP-70 enhances BCR signaling in CLL cells independently of its kinase activity [11]. BCR signaling is also dependent on the type of antigen encountered. CLL cells express an excessively restricted and biased IGHV gene repertoire and in certain instances share identical or stereotyped HCDR3 sequences [8,12–14]. The latter is reminiscent of immunoglobulin that binds to common antigen(s), which initially select and drive the CLL clone ontogeny and later enable clonal proliferation and survival. Accordingly, the BCR in CLL is often poly-reactive and assumed to bind microbial epitopes or auto-antigens uncovered on the membrane of apoptotic cells [15–17].

In this issue of Leukemia and Lymphoma, Wang and colleagues evaluated another aspect of BCR signaling in CLL [18]. They quantified levels of expression of genes involved in BCR signaling in CLL cells and correlated them with a variety of well recognized prognostic parameters and eventual clinical outcome. It appears that mRNA levels of Lyn, spleen tyrosine kinase (Syk), phospholipase Cγ2 (PLCγ2) and ERK measured at diagnosis of CLL are strongly associated with each other. Of all the genes studied, it appears that Lyn is correlated best with the clinical course of the disease. Lyn mRNA levels were increased in patients with CLL who eventually required treatment compared to those who did not need therapy [18]. Higher mRNA expression of Lyn also significantly correlated with a shorter time to first treatment from the time of diagnosis, but this statistical significance was lost in a multivariate analysis comparing other well established prognostic factors in CLL. The findings described by Wang and colleagues are interesting and potentially important in CLL, but are somewhat limited because they lack validation at the protein level, were not compared to normal B-cells and no functional data are provided on how Lyn “overexpression” may potentiate BCR signaling in CLL.

Lyn is a Src-related tyrosine kinase and plays a key role in BCR signaling. Antigen engagement of the BCR receptor induces coordinated downstream cascades, and one of these initial pivotal events consists of the recruitment of Lyn to phosphorylate the immunoreceptor tyrosine-based activation motifs (ITAMs) of the Igα/Igβ components of the BCR. Thereafter, additional kinases and adaptor molecules such as Syk, PLCγ2, phosphatidylinositol 3-kinases (PI3K), Bruton's tyrosine kinase (Btk), Vav and B-cell linker (Blnk) are also recruited and activated, to form microsignalosomes which amplify the BCR signal and activate various downstream signaling pathways. Lyn protein is known to be overexpressed in CLL cells [19]; however, its mRNA levels appear to be similar to those found in normal B-cells. In CLL cells Lyn is abnormally localized and constitutively active, while in resting normal B-cells it is in an inactive form [19]. In this respect, IgM ligation in CLL cells results only in slight increases in Lyn activity, whereas it markedly increases in normal B-lymphocytes [19]. This constitutive Lyn activity seen in CLL cells may be explained by an ongoing BCR signaling in CLL [19], and it is not that surprising that blocking intracellular Lyn activity results in decreased tyrosine phosphorylation and apoptosis in CLL cells [19].

In this regard, improved understanding of the central role of BCR signaling in CLL has led to the concept that the BCR signalosome could be utilized as a possible target for therapy. Small-molecule drugs, targeting signaling molecular pathways downstream of the BCR such as Lyn, Syk, Btk or PI3K isoform p110delta (PI3Kdelta), have recently shown encouraging clinical activity in CLL [20–22], and will probably become part of the molecular therapy for this disease in the future.

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