Role of Bruton's tyrosine kinase in B cells and malignancies

Abstract

Bruton's tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies. In particular, the orally administered irreversible BTK inhibitor ibrutinib is associated with high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle-cell lymphoma (MCL), including patients with high-risk genetic lesions. Because ibrutinib is generally well tolerated and shows durable single-agent efficacy, it was rapidly approved for first-line treatment of patients with CLL in 2016. To date, evidence is accumulating for efficacy of ibrutinib in various other B cell malignancies. BTK inhibition has molecular effects beyond its classic role in BCR signaling. These involve B cell-intrinsic signaling pathways central to cellular survival, proliferation or retention in supportive lymphoid niches. Moreover, BTK functions in several myeloid cell populations representing important components of the tumor microenvironment. As a result, there is currently a considerable interest in BTK inhibition as an anti-cancer therapy, not only in B cell malignancies but also in solid tumors. Efficacy of BTK inhibition as a single agent therapy is strong, but resistance may develop, fueling the development of combination therapies that improve clinical responses. In this review, we discuss the role of BTK in B cell differentiation and B cell malignancies and highlight the importance of BTK inhibition in cancer therapy.

Keywords: B cell development; B cell receptor signaling; Bruton’s tyrosine kinase; Chemokine receptor; Chronic lymphocytic leukemia; Ibrutinib; Leukemia; Lymphoma; Tumor microenvironment.

Fig. 1

Domain structure of TEC kinase family members and key interacting partners of Bruton’s tyrosine kinase. a Schematic overview of the protein structure of BTK and other TEC kinase family members. Shown are five different domains, as explained in text, the Y223 autophosphorylation site, the Y551 phosphorylation site that activates BTK, and the C481 binding site of ibrutinib. b Schematic overview of the protein structure of key interacting partners of BTK. PH, pleckstrin homology; TH, TEC homology; BH, BTK homology; PRR, proline rich domain; SH2/SH3, SRC homology domains 2 and 3; Cys, cysteine-string motif

Fig. 2

Role of Bruton’s tyrosine kinase downstream of the B cell receptor. Signaling cascade showing important events downstream of B cell receptor (BCR). Antigen engagement by the BCR results in the formation of a micro-signalosome whereby BTK activates four families of non-receptor protein tyrosine kinases that transduce key signaling events including phospholipase Cγ, mitogen-activated protein kinase (MAPK) activation, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) pathway components and activation of the serine/threonine kinase AKT (PKB). In addition, BTK mediated signaling events are regulated by various phosphatases that can be recruited to the cell membrane, following crosslinking of inhibitory receptors, e.g., FcγRIIB that is exclusively expressed on B cells and signals upon immune complex binding. See text for details

Fig. 3

Role of Bruton’s tyrosine kinase downstream of chemokine receptors, Toll-like receptors and activating Fcγ receptors. Signaling cascade showing important events downstream of (a) Chemokine receptors (e.g. CXCR4): upon chemokine binding to the extracellular domain Gα and Gβy subunits can independently activate PI3K, which results in activation of BTK, AKT and MAPK-dependent pathways. b Toll-like receptors: upon ligand recognition TLRs recruit different proteins including TIR, MYD88, IRAK1 and TIRAP/MAL, all of which interact with BTK and induce downstream activation of the transcription factor NF-κB. c Activating Fc receptors (e.g. FcγRI): Following FcγRI cross-linking, Src-kinases, SYK, PI3K-γ and BTK are activated. In contrast, inhibitory Fc-receptors (FcγRIIB) containing ITIM domains recruit phosphatases and reduce BTK activation (Fig. 2). See text for details

Fig. 4

Stages of B cell differentiation and associated malignancies. Model of B cell development indicating different stages of B cell differentiation and important immune checkpoints where BTK plays a key role. Various B-cell malignancies are indicated, which are associated with abnormal BTK signaling at distinct stages of B-cell differentiation and activation. Note that the cellular origin of U-CLL is thought to be CD5⁺ mature B cells. Somatic hypermutation status of BCR and gene expression profiling indicates post-germinal center (GC) origin of M-CLL. See text for detailed information. CLP, common lymphoid progenitor; CSR, class switch recombination; FDC, follicular dendritic cell; SHM, somatic hypermutation