Abnormal centrosome-centriole cycle in chronic myeloid leukaemia?
Abnormal numbers, structures and functions of centrosomes in chronic myeloid leukaemia (CML) may influence cell proliferation and genomic instability, which are features of the disease. Centrosomes are regulators of mitotic spindle orientation and can act as scaffolds for centrosome-associated regulators of the cell cycle. This study showed, for the first time, that p210(BCR-ABL1) and p145(ABL1) are both centrosome-associated proteins, as demonstrated by co-immunoprecipitation with the pericentriolar protein, pericentrin. Furthermore, when CML cells were treated with imatinib there was a 55% and 20% reduction of p210(BCR-ABL1) and p145(ABL1) binding to pericentrin, respectively. Cell lines expressing p210(BCR-ABL1) and primary CD34(+) cells from CML patients exhibited more numerical and structural centrosomal abnormalities than p210(BCR-ABL1) negative cells. Primary cells from CML blast crisis (BC) patients exhibited a distinctive amorphous staining pattern of pericentrin compared to normal and CML chronic phase (CP) patients, suggesting a possible defect in pericentrin localisation at the centrosomes. Proteins, such as aurora kinases, pericentrin, survivin and separase, regulate centrosome structure and function, cell cycle and mitotic spindle formation. Levels of the protease, separase are abnormally high in CML CP and BC cells in comparison to normal CD34(+) cells. The data imply that expression of p210(BCR-ABL1) is associated with abnormalities in the centrosome-centriole cycle and increased separase expression.
Patel
Hetal
H
Faculty of Medicine, Department of Haematology, Imperial College, Hammersmith Campus, London, UK. hetal.patel@imperial.ac.uk
Gordon
Myrtle Y
MY
D000941:Antigens / Q000032:analysis / Q000378:metabolism; D064127:Aurora Kinases; D001549:Benzamides; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001752:Blast Crisis / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western / Q000379:methods; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000032:analysis; D002502:Centrioles / Q000378:metabolism / Q000502:physiology; D018385:Centrosome / Q000737:chemistry / Q000502:physiology*; D010450:Endopeptidases / Q000032:analysis; D005434:Flow Cytometry / Q000379:methods; D005455:Fluorescent Antibody Technique; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D047468:Immunoprecipitation; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051034:Inhibitor of Apoptosis Proteins; D020014:K562 Cells; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000032:analysis; D010879:Piperazines / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D064247:Separase; D018709:Statistics, Nonparametric; D000077022:Survivin
D000941:Antigens; C107489:BIRC5 protein, human; D001549:Benzamides; D015415:Biomarkers; D018797:Cell Cycle Proteins; D007166:Immunosuppressive Agents; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D010879:Piperazines; D011743:Pyrimidines; D000077022:Survivin; C086178:pericentrin; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016044:Fusion Proteins, bcr-abl; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D010450:Endopeptidases; C577987:ESPL1 protein, human; D064247:Separase