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.

Effects of BTK signalling in pathogenic microorganism infections

“…Every domain of Btk has a site for specific molecules to participate in various signalling pathways related to different physiological activities, which makes Btk function complex and variable. Meanwhile, Btk, Tec and Itk partially overlap not only in expression patterns but also in functions, and Tec has been reported to partially compensate for Btk functions in mice . Although the effects of Btk signalling on pathogenic microorganism infections are not exactly consented upon, there is no doubt about its importance in maintaining the balance of the immune microenvironment.…”

“…Btk is generally expressed in all haematopoietic lineages except for T cells and plasma cells, including B cells and all innate immune cells . Notably, Btk expression in the B cell lineage occurs in a developmental fashion, which shows inconformity during the different stages of B cell development from marrow‐derived haematopoietic stem cells to resting mature cells . In addition, some evidence indicates that Btk may also be expressed in solid tumours.…”

“…Lacking functional circulating B lymphocytes, individuals cannot generate any immunoglobulins in response to antigenic stimulations to develop an effective humoural immune response . Btk dramatically and extensively affects all stages of B cell development, including proliferation, maturation, differentiation, apoptosis and cell migration . Recent studies have increasingly focused on the awareness of Btk roles in other innate immune cells, such as macrophages, dendritic cells (DCs) and neutrophils .…”

Morphology‐ and Size‐Controlled Fabrication of CdS from Flower‐Like to Spherical Structures and their Application for High‐Performance Photoactivity

“…As well known, the control over the morphology of semiconductors remains an important goal in modern synthetic chemistry, which is the model system for basic research. Hence, enormous efforts have been devoted in the production of CdS micro‐and nanostructures with controlled morphologies such as flower‐like structure, nanobelts, nanowires and nanosphere, which guarantee the attractive physical and chemical properties . For example, Yu et al have synthesized the morphology‐controlled CdS photocatalysts by adjusting the sulfur source and solvent, explaining the formation mechanism and influence of different morphologies and the nature of solvents on the activity .…”

A novel Bruton's tyrosine kinase inhibitor, acalabrutinib, suppresses osteoclast differentiation and Porphyromonas gingivalis lipopolysaccharide‐induced alveolar bone resorption

“…The most well‐known function of BTK is the role in B cell receptor signaling, in which its deficiency results in the lack of circulating B cells and humoral immune responses as shown in X‐linked agammaglobulinemia (XLA) patients . In addition, recent evidence indicates that BTK is also involved in B cell malignancies . Indeed, the pharmacologic intervention of BTK by ibrutinib has been approved to treat mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenstrom macroglubulinemia .…”