Signaling Networks Associated With BCR-ABL-Dependent Transformation
Signaling Networks Associated With BCR-ABL-Dependent Transformation
Background: The fusion protein BCR-ABL results in constitutive tyrosine kinase activity. It also affects downstream targets as well as the subcellular location of the normally tightly regulated Abl tyrosine kinase.
Methods: The authors review the current knowledge concerning the signaling networks associated with BCR-ABL–dependent transformation.
Results: Although BCR-ABL is considered a single genetic change, the dysregulated tyrosine kinase activates a network of signals that contributes to cytokine-independent growth, resistance to apoptosis, and genetic instability.
Conclusions: The effectiveness of BCR-ABL–dependent transformation of hematopoietic stem cells is due not to a single pathway but rather to the culmination of a network of signaling pathways.
The cytogenetic hallmark of the presence of BCR-ABL–positive tumors is the detection of the Philadelphia chromosome. This cytogenetic abnormality is due to the reciprocal translocation of chromosomes 9 and 22 [t(9:22)]. This translocation results in the fusion of the breakpoint cluster region (BCR) gene located on chromosome 22 and c-Abl gene located on chromosome 9 (Fig 1). The corresponding protein is referred to as BCR-ABL. Three predominant products are formed depending on which breakpoint located within the BCR gene is fused with exon a2 of ABL. The corresponding fusion protein will encode either a p190, p210, or p230 molecular weight protein (Fig 2). These oncogene products are associated with a specific type of leukemia, suggesting that their respective transforming capacities are distinct. In the majority of patients with chronic myelogenous leukemia (CML) and in approximately one-third of those with Ph+ acute lymphoblastic leukemia (ALL), the break occurs within the area spanning exon 12–16, often referred to as b1b5 and defined as the major breakpoint cluster region (M-BCR). The corresponding mRNA referred to as b2a2 and b3a2 is translated into a fusion protein commonly known as p210 BCR-ABL The minor breakpoint, referred to as m-BCR, occurs between exons e1 and e2. The corresponding e1a2 mRNA is translated into a 190-kd fusion protein and is present in the remaining Ph+ ALL patients and rarely in patients with CML. More recently, a third breakpoint, μ-BCR, was identified. It is located downstream of exon e19, giving rise to the e19a2 fusion product. The corresponding protein consists of a 230-kd fusion protein and is considered a rare event found in Ph+ chronic neutrophilic leukemia. Consistent with clinical findings, in vitro and transgenic studies have shown that expression of p190, p210, and p230 has distinct phenotypes. In particular, p190 had the shortest latency period, and mice developed B-cell origin leukemia exclusively. In contrast, p210 transgenic mice typically developed leukemia of B-, T-lymphoid,or myeloid origin. Finally, p230 transgenic mice showed the longest latency period and exhibited a less aggressive tumor, a finding that is consistent with the clinical disease. This review focuses on the contribution of p210 BCR-ABL typically found in CML in mediating cell growth and cell survival.
Abstract and Introduction
Abstract
Background: The fusion protein BCR-ABL results in constitutive tyrosine kinase activity. It also affects downstream targets as well as the subcellular location of the normally tightly regulated Abl tyrosine kinase.
Methods: The authors review the current knowledge concerning the signaling networks associated with BCR-ABL–dependent transformation.
Results: Although BCR-ABL is considered a single genetic change, the dysregulated tyrosine kinase activates a network of signals that contributes to cytokine-independent growth, resistance to apoptosis, and genetic instability.
Conclusions: The effectiveness of BCR-ABL–dependent transformation of hematopoietic stem cells is due not to a single pathway but rather to the culmination of a network of signaling pathways.
Introduction
The cytogenetic hallmark of the presence of BCR-ABL–positive tumors is the detection of the Philadelphia chromosome. This cytogenetic abnormality is due to the reciprocal translocation of chromosomes 9 and 22 [t(9:22)]. This translocation results in the fusion of the breakpoint cluster region (BCR) gene located on chromosome 22 and c-Abl gene located on chromosome 9 (Fig 1). The corresponding protein is referred to as BCR-ABL. Three predominant products are formed depending on which breakpoint located within the BCR gene is fused with exon a2 of ABL. The corresponding fusion protein will encode either a p190, p210, or p230 molecular weight protein (Fig 2). These oncogene products are associated with a specific type of leukemia, suggesting that their respective transforming capacities are distinct. In the majority of patients with chronic myelogenous leukemia (CML) and in approximately one-third of those with Ph+ acute lymphoblastic leukemia (ALL), the break occurs within the area spanning exon 12–16, often referred to as b1b5 and defined as the major breakpoint cluster region (M-BCR). The corresponding mRNA referred to as b2a2 and b3a2 is translated into a fusion protein commonly known as p210 BCR-ABL The minor breakpoint, referred to as m-BCR, occurs between exons e1 and e2. The corresponding e1a2 mRNA is translated into a 190-kd fusion protein and is present in the remaining Ph+ ALL patients and rarely in patients with CML. More recently, a third breakpoint, μ-BCR, was identified. It is located downstream of exon e19, giving rise to the e19a2 fusion product. The corresponding protein consists of a 230-kd fusion protein and is considered a rare event found in Ph+ chronic neutrophilic leukemia. Consistent with clinical findings, in vitro and transgenic studies have shown that expression of p190, p210, and p230 has distinct phenotypes. In particular, p190 had the shortest latency period, and mice developed B-cell origin leukemia exclusively. In contrast, p210 transgenic mice typically developed leukemia of B-, T-lymphoid,or myeloid origin. Finally, p230 transgenic mice showed the longest latency period and exhibited a less aggressive tumor, a finding that is consistent with the clinical disease. This review focuses on the contribution of p210 BCR-ABL typically found in CML in mediating cell growth and cell survival.