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Cited by 742Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentImmunodeficiency and Autoimmune Disorders

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

Open access
Pal Singh, Simar, Dammeijer, Floris, Hendriks, Rudi W.·2018·Molecular Cancer
DOI 10.1186/s12943-018-0779-zPMC PMC5817726
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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.

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Figures

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. 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 motifCC BY · PubMed Central
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. 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 detailsCC BY · PubMed Central
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. 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 detailsCC BY · PubMed Central
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
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 hypermutationCC BY · PubMed Central

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Metadata

Authors
Pal Singh, S., Dammeijer, F., & Hendriks, R. W.
Affiliations
Erasmus MC (NL)
Corresponding author
Hendriks, Rudi W.
ORCID
Venue
Molecular Cancer
Publisher
Springer Science and Business Media LLC
Published
2018-02-19
Volume
17
Issue
1
Pages
57-57
ISSN
1476-4598 (ISSN-L)
DOI
10.1186/s12943-018-0779-z
PMC
PMC5817726
OpenAlex
W2791299132
Cited by
726
References
272
Citations by year
2026: 62 · 2025: 89 · 2024: 123 · 2023: 104 · 2022: 127 · 2021: 100 · 2020: 67 · 2019: 45 · 2018: 9
FWCI
8.03
Type
journal article
Language
en
Update notices
correction (2019-04-03)
Open access
Licence
Locations
  • Molecular Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
ZonMw
Topics
  • Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
Keywords
Bruton's tyrosine kinase, B-cell malignancies, ibrutinib, chronic lymphocytic leukemia, mantle cell lymphoma, B cell receptor signaling, X-linked agammaglobulinemia, B cell differentiation, BTK inhibitors, tumor microenvironment, myeloid cells, drug resistance, combination therapy, solid tumors
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Animals, Antineoplastic Combined Chemotherapy Protocols, B-Lymphocytes, Bone Marrow, Cell Differentiation, Cell Transformation, Neoplastic, Humans, Receptors, Antigen, B-Cell, Biomarkers, Tumor, Signal Transduction, Leukemia, B-Cell, Gene Expression Regulation, Neoplastic, Lymphoma, B-Cell, Treatment Outcome, Lymphopoiesis, Protein Kinase Inhibitors, Molecular Targeted Therapy, Tumor Microenvironment

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