Chronic myelogenous leukemia (CML) requires the BCR/ABL tyrosine kinase for disease onset and maintenance. As a result, CML can be successfully treated with tyrosine kinase inhibitors (TKIs) such as imatinib. Most patients are maintained in a disease-suppressed state on daily TKI therapy for several years and in many cases this treatment prevents progression to the blast phase. If the TKI is di...

Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimul...

The presence of BCR-ABL fusion genes has important diagnostic and prognostic implications in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The CML-specific chimeric BCR-ABL gene with a break involving the major breakpoint cluster region (M-bcr) of the BCR-gene has been detected by means of fluorescence in situ hybridization (FISH). In this study, we present a FISH proto...

Lipocalin 24p3 is a secreted protein that can induce apoptosis in cells containing the 24p3 cell surface receptor, 24p3R. The oncoprotein BCR-ABL activates 24p3 and represses 24p3R expression. Thus, BCR-ABL(+) cells synthesise and secrete 24p3, which induces apoptosis in normal 24p3R-containing cells but not in BCR-ABL(+) cells. The cell signalling and transcription factor pathways by which BCR...

BACKGROUND AND OBJECTIVES We previously described a novel type of the chimeric bcr-abl mRNA transcript in a patient with a Philadelphia chromosome positive chronic myeloid leukemia. A similar bcr-abl transcript has also been described by others. DESIGN AND METHODS Sequence analysis of the fusion region showed a join between part of exon e8 of the bcr gene and an intronic sequence of abl intro...

The Wnt signalling pathway can activate transcription of genes such as c-myc through beta-catenin. Here, we describe the protein breakpoint cluster region, Bcr, as a negative regulator of this pathway. Bcr can form a complex with beta-catenin and negatively regulate expression of c-Myc. Knockdown of Bcr by short interfering RNA relieves the block and activates expression of c-Myc. Expression of...

The abundance of the BCR/ABL protein critically contributes to CML pathogenesis and drug resistance. However, understanding of molecular mechanisms underlying BCR/ABL gene regulation remains incomplete. While BCR/ABL kinase inhibitors have shown unprecedented efficacy in the clinic, most patients relapse. In this study, we demonstrated that the Sp1 oncogene functions as a positive regulator for...

Levels of AgR (BCR) expression are regulated during B cell development, activation, and induction of tolerance. The mechanisms responsible for and consequences of this regulation are poorly understood. We have described a class of DNA-based autoantigen-reactive B cell that down-regulates BCR expression during development to mature follicular phenotype. In this study, we show that at immature st...

The Philadelphia (Ph) chromosome, the product of t(9:22), is the cytogenetic hallmark of chronic myelogenous leukemia. The c-abl oncogene on chromosome 9 is translocated to the Ph chromosome and linked to a breakpoint cluster region (bcr), which is part of a large bcr gene. This results in the formation of a bcr-c-abl fusion gene, which is transcribed into an 8.5 kb chimeric mRNA encoding a 210...

In Chronic Myeloid Leukemia 80% of patients present alternative splice variants involving BCR exons 1, 13 or 14 and ABL exon 4, with a consequent impairment in the reading frame of the ABL gene. Therefore BCR/ABL fusion proteins (BCR/ABL-OOF) are characterized by an in-frame BCR portion followed by an amino acids sequence arising from the out of frame (OOF) reading of the ABL gene. The product ...