The Bruton's tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages

Abstract

X-linked agammaglobulinemia (XLA) is an immunodeficiency disease in man, resulting from an arrest in early B cell differentiation. The gene defective in XLA has recently been identified and encodes a cytoplasmic protein tyrosine kinase, named Bruton's tyrosine kinase (btk), essential for cell differentiation and proliferation at the transition from pre-B to later B cell stages. In this study we investigated btk expression by Northern blotting experiments in a series of human (precursor-) B cell lines, acute lymphoblastic leukemias and plasmacytomas. btk was found to be already expressed in very early stages of B cell differentiation, even prior to immunoglobulin (Ig) heavy (H) or light (L) chain gene rearrangements. Transcripts were also detected at the pre-B cell stage and in mature B cells, irrespective of the Ig H chain class expressed. Approximately at the transition from mature B cells to plasma cells, expression of the btk gene is down-regulated. In addition, the btk gene was found to be expressed in myeloid cell lines and acute myeloid leukemias. btk expression in myeloid cells is probably not a prerequisite for myeloid differentiation, since myeloid cells in XLA patients seem not to be affected. No btk expression was found in T-lineage cells. The btk expression profile, i.e. from early precursor-B cell stages preceding Ig rearrangement up to mature B cells, supports the hypothesis that the XLA defect resides in a critical step of B cell development which is independent of the Ig gene recombination machinery.

The protein product of the c-cbl protooncogene is phosphorylated after B cell receptor stimulation and binds the SH3 domain of Bruton's tyrosine kinase.

“…The identification of Btk as a member of the nonreceptor tyrosine kinase family, a family of proteins already established as being involved in hematopoietic signal transduction, fits well with the disease phenotype of XLA. The Btk protein is expressed in early and mature human B cell lines but is absent in terminally differentiated plasma cell lines, which is consistent with the requirement of a functional Btk protein for normal B cell differentiation (4)(5)(6). There is now evidence from a variety of sources to suggest that Btk is one of the many tyrosine kinases involved in B cell receptor (BCK) signal transduction.…”

Posttranscriptional regulation of Bruton's tyrosine kinase expression in antigen receptor-stimulated splenic B cells

“…Bruton's tyrosine kinase (Btk) is a signal transducing protein expressed in all hematopoietic lineages, except T cells (6)(7)(8)(9)(10). Btk has a particularly important role in B lymphocytes, where it functions in multiple receptor pathways, including the B cell antigen receptor (BCR), interleukin 5 and 10 receptors, CD19, CD38, and CD40 (11).…”

Correction of the X-linked immunodeficiency phenotype by transgenic expression of human Bruton tyrosine kinase under the control of the class II major histocompatibility complex Ea locus control region

“…Using a human Btk (hBtk) cDNA clone phBtk2.55, which was isolated from a pro-B cell cDNA library (24), the 5Ј end of the cDNA up to the EcoRI site at cDNA position 1453 (1) was subcloned by EcoRI digestion and religation (phBtk1.45). A 670-bp EcoRI-blunted HindIII fragment (positions 1453-2123) from phBtk2.55 was cloned into EcoRI and EcoRV digested phBtk1.45.…”

“…Btk is expressed throughout B cell differentiation, except in plasma cells (8,13,24). Although Btk is already present in pro-B cells, the first selective disadvantage of Btk-deficient cells only becomes apparent at the transition from small pre-B cells to immature B cells in the bone marrow (13).…”