Abstract
Multistep carcinogenesis is exemplified by chronic myeloid leukemia with clinical manifestation consisting of a chronic phase and blast crisis. Pathological generation of BCR-ABL (breakpoint cluster region-Abelson) results in growth promotion, differentiation, resistance to apoptosis, and defect in DNA repair in targeted blood cells. Domains in BCR and ABL sequences work in concert to elicit a variety of leukemogenic signals including Ras, STAT5 (signal transducer and activator of transcription-5), Myc, cyclin D1, P13 (phosphatidylinositol 3-kinase), RIN1 (Ras interaction/interference), and activation of actin cytoskeleton. However, the mechanism of differentiation of transformed cells is poorly understood. A mutator phenotype of BCR-ABL could explain the transformation to blast crisis. The aim of this review is to integrate molecular and biological information on BCR, ABL, and BCR-ABL and to focus on how signaling from those molecules mirrors the biological phenotypes of chronic myeloid leukemia.
MeSH terms
-
Animals
-
Blast Crisis / genetics
-
Cell Differentiation
-
Cell Transformation, Neoplastic / genetics
-
Disease Progression
-
Fusion Proteins, bcr-abl / chemistry
-
Fusion Proteins, bcr-abl / genetics*
-
Fusion Proteins, bcr-abl / physiology
-
Gene Expression Regulation, Leukemic
-
Genes, abl
-
Humans
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
-
Leukemia, Myeloid, Accelerated Phase / genetics
-
Leukemia, Myeloid, Chronic-Phase / genetics
-
Mice
-
Mice, Knockout
-
Models, Biological
-
Neoplasm Proteins / physiology
-
Neoplastic Stem Cells / enzymology
-
Neoplastic Stem Cells / pathology
-
Oncogene Proteins / chemistry
-
Oncogene Proteins / genetics
-
Oncogene Proteins / physiology
-
Phenotype
-
Philadelphia Chromosome
-
Phosphorylation
-
Protein Processing, Post-Translational
-
Protein Structure, Tertiary
-
Protein-Tyrosine Kinases*
-
Proto-Oncogene Proteins c-abl / chemistry
-
Proto-Oncogene Proteins c-abl / genetics
-
Proto-Oncogene Proteins c-abl / physiology
-
Proto-Oncogene Proteins c-bcr
-
Proto-Oncogene Proteins*
-
Rats
-
Signal Transduction
-
Structure-Activity Relationship
Substances
-
Neoplasm Proteins
-
Oncogene Proteins
-
Proto-Oncogene Proteins
-
Protein-Tyrosine Kinases
-
Fusion Proteins, bcr-abl
-
Proto-Oncogene Proteins c-abl
-
BCR protein, human
-
Bcr protein, mouse
-
Proto-Oncogene Proteins c-bcr