Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia

Abstract

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 kd bcr-c-abl fusion protein. The Ph chromosome is also found in acute lymphoblastic leukemia (Ph+ ALL). Although the c-abl is translocated and a new 190 kd c-abl protein has been identified, no breakpoints are observed in the bcr (Ph+bcr- ALL). Here we show that in Ph+bcr- ALL, breakpoints in chromosome 22 occur within the same bcr gene, but more 5' of the bcr. Cloning of a chimeric bcr-c-abl cDNA demonstrates that the fusion gene is transcribed into a 7 kb mRNA, encoding a novel fusion protein.

Detection of fusion genes at the protein level in leukemia patients via the flow cytometric immunobead assay

“…The first identified bcr was the socalled "major bcr" (M-bcr), which is predominantly involved in CML patients and results in the BCR-ABL p210 fusion protein. Later, the so-called "minor bcr" (m-bcr) was identified, occurring mostly in adult BCP-ALL patients and resulting in the BCR-ABL p190 fusion protein (Table 1) [4][5][6][7]. In addition to these two common breakpoints, several less frequent breakpoint variants have been found, such as m-bcr, vbcr, etc.…”

“…The first chromosome aberration discovered in leukemia patients was the so-called Philadelphia (Ph) chromosome, which was shown to result from the (9;22) translocation, in which the BCR gene is aberrantly coupled to the ABL1 gene [4,5]. The t(9;22) is found in virtually all patients with chronic myeloid leukemia (CML) and in a fraction of the patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), particularly in adults [6].…”

Review of clinical, cytogenetic, and molecular aspects of Ph-negative CML

“…Both the RNAse protection assay and PCR technique give the opportunity to identify which BCR exou is fused to abl. In CML patients with t(9:22), usually BCR exon 2 (b2) or BCR exon 3 (b3) is fused to ablexon 2 (a2), restlltingin b2a2 orb3a2 t)cr abl fusion region [36]. The results of these molecular investigations are presented in detail in Tables 3-6 together with the corresponding cytogenetic data.…”

Bcr phosphorylated on tyrosine 177 binds Grb2

“…Recent studies indicate that the DBL homology domain within Bcr is functional (Chuang et al, 1995). Patients acquiring the Ph fuse 5' sequences of BCR to the bulk of the ABL gene (Shtivelman et al, 1986;Hermans et al, 1987). The resulting Bcr-Abl oncoprotein contains either 426 amino acids of Bcr or 902/926 amino acids of Bcr fused to the Abl protein lacking the ®rst exon coding sequences (Shtivelman et al, 1987).…”