Chronic Lymphocytic Leukemia: Disease Biology

Abstract

Background: B-cell receptor (BCR) signaling is crucial for normal B-cell development and adaptive immunity. In chronic lymphocytic leukemia (CLL), the malignant B cells display many features of normal mature B lymphocytes, including the expression of functional B-cell receptors (BCRs). Cross talk between CLL cells and the microenvironment in secondary lymphatic organs results in BCR signaling and BCR-driven proliferation of the CLL cells. This critical pathomechanism can be targeted by blocking BCR-related kinases (BTK, PI3K, spleen tyrosine kinase) using small-molecule inhibitors. Among these targets, Bruton tyrosine kinase (BTK) inhibitors have the highest therapeutic efficacy; they effectively block leukemia cell proliferation and generally induce durable remissions in CLL patients, even in patients with high-risk disease. By disrupting tissue homing receptor (i.e., chemokine receptor and adhesion molecule) signaling, these kinase inhibitors also mobilize CLL cells from the lymphatic tissues into the peripheral blood (PB), causing a transient redistribution lymphocytosis, thereby depriving CLL cells from nurturing factors within the tissue niches.

Summary: The clinical success of the BTK inhibitors in CLL underscores the central importance of the BCR in CLL pathogenesis. Here, we review CLL pathogenesis with a focus on the role of the BCR and other microenvironment cues.

Key messages: (i) CLL cells rely on signals from their microenvironment for proliferation and survival. (ii) These signals are mediated by the BCR as well as chemokine and integrin receptors and their respective ligands. (iii) Targeting the CLL/microenvironment interaction with small-molecule inhibitors provides a highly effective treatment strategy, even in high-risk patients.

Keywords: B-cell receptor; BTK; Chemokine receptors; Chronic lymphocytic leukemia; Ibrutinib; Microenvironment; Nurse-like cells; PI3K; Spleen tyrosine kinase.

Fig. 1.

Composition of the CLL microenvironment. CLL cells rely on a multitude of signals from the tissue microenvironment in SLO to promote their survival and proliferation. These signals are received through CLL surface receptors that are engaged by corresponding microenvironmental ligands, including signals from the BCR, CD40, chemokine receptors (CXCR4, CXCR5), and adhesion molecules, such as integrins, and TNF-family receptors including BAFF-R, TACI, and BCMA. BTK inhibitors inhibit several of these signaling cascades and effectively disrupt the cross-talk between CLL cells and the microenvironment, thereby depriving them from essential survival factors, and disrupting tissue homing signals, resulting in mobilization of tissue CLL cells from SLO into the PB.

Fig. 2.

CLL BCR subsets and BCR signaling inhibitors. a CLL patients can be distinguished based on the mutational status of IGHV gene sequences with the variable region of the BCR heavy chains (V_H) and categorized into U-CLL or M-CLL, which differ in terms of activation properties and antigen affinity and selectivity, as highlighted in the figure. b Engagement of the BCR results in the activation of the receptor-associated kinases LYN and SYK which further propagate the signal via BTK, PI3K, and PLCg2. This ultimately results in the activation of ERK and NFkB and the modulation of their transcriptional targets. The BCR-associated kinases also serve as important hubs for signals emanating from receptors other than the BCR, such as integrin and chemokine receptors. SYK, PI3K, and BTK are targets for small-molecule kinase inhibitors, including the SYK inhibitor fostamatinib (not approved), the BTK kinase inhibitors ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, and the PI3K inhibitors idelalisib and duvelisib.