Activation of hematopoietic growth factor signal transduction pathways by the human oncogene BCR/ABL.
BCR/ABL is a human chimeric oncogene that causes chronic myelogenous leukemia (CML). The BCR/ABL oncogene is generated from the Philadelphia chromosome (Ph) translocation, t(9;22)(q34;q11), and creates a constitutively active tyrosine kinase. There is clonal expansion of hematopoietic stem cells of several different lineages in CML. CML patients in stable phase usually have high white blood counts and immature cells of granulocytic lineages. Stable phase CML evolves to a more aggressive phase typically within 3.5-5 years, where differentiation is blocked and acute leukemia ensues. The transition of CML stable phase to blast phase is reflected in the loss of growth factor requirement of CML cells and correlates with additional cytogenetic alterations. Some biological effects reported in primary CML cells include reduced apoptosis and altered adhesion to fibronectin; however, the cells are dependent on hematopoietic growth factors. On a molecular level, the BCR/ABL translocation is well characterized. However, the actual mechanism of transformation by the BCR/ABL oncogene of hematopoietic cells is largely unknown. Enhancement of the c-ABL tyrosine kinase activity in BCR/ABL appears to be crucial for transformation. This tyrosine kinase activity leads to activation of several signal transduction pathways that are also utilized by hematopoietic growth factors, including steel factor, thrombopoietin, interleukin-3, and granulocyte/macrophage-colony stimulating factor. In several model systems, BCR/ABL has overlapping biological effects with hematopoietic growth factors, and transformation of hematopoietic growth factor-dependent cell lines leads to growth factor independence. In this review, we will describe the molecular and biological abnormalities in CML and several signal transduction mechanisms utilized by BCR/ABL as compared to hematopoietic growth factors.
Sattler
M
M
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Martin_Sattler@DFCI.HARVARD.EDU
Salgia
R
R
D048868:Adaptor Proteins, Signal Transducing; D002448:Cell Adhesion; D002471:Cell Transformation, Neoplastic; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology; D016313:Genes, abl; D016298:Hematopoietic Cell Growth Factors / Q000235:genetics* / Q000502:physiology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology / Q000235:genetics; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases; D018631:ras Proteins / Q000235:genetics / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D016298:Hematopoietic Cell Growth Factors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D016044:Fusion Proteins, bcr-abl; D018631:ras Proteins; C067419:CBL protein, human