Molecular biology of chronic myeloid leukemia.
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.
Maru
Y
Y
Department of Genetics, Institute of Medical Science, University of Tokyo, Japan. ymaru@ims.u-tokyo.ac.jp
D000818:Animals; D001752:Blast Crisis / Q000235:genetics; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D016313:Genes, abl; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015465:Leukemia, Myeloid, Accelerated Phase / Q000235:genetics; D015466:Leukemia, Myeloid, Chronic-Phase / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D010677:Philadelphia Chromosome; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D051562:Proto-Oncogene Proteins c-bcr; D051381:Rats; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; C496613:BCR protein, human; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr