Abstract
The 8;21 chromosomal translocation occurs in 15% to 40% of patients with the FAB M2 subtype of acute myeloid leukemia (AML). This chromosomal abnormality fuses part of the AML1/RUNX1 gene to the ETO/MTG8 gene and generates the AML1-ETO protein. We previously identified a C-terminal truncated AML1-ETO protein (AEtr) in a mouse leukemia model. AEtr is almost identical to the AML1-ETO exon 9a isoform expressed in leukemia patients. Here, we describe a novel function of AEtr in the development of aneuploidy through spindle checkpoint attenuation. AEtr cells had a reduced mitotic index following nocodazole treatment, suggesting a failure in a subset of cells to arrest in mitosis with a functional spindle checkpoint. Additionally, primary leukemia cells and cell lines expressing AEtr were aneuploid. Moreover, AEtr cells had reduced levels of several spindle checkpoint proteins including BubR1 and securin following treatment with the spindle poison nocodazole. These results suggest that inactivation of the spindle checkpoint may contribute to the development of aneuploidy described in t(8;21) leukemia patients.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Aneuploidy*
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Animals
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Antineoplastic Agents / pharmacology
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Cell Cycle Proteins / biosynthesis*
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Cell Cycle Proteins / genetics
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Cell Cycle* / drug effects
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Cell Cycle* / genetics
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Chromosomes, Human, Pair 21 / genetics
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Chromosomes, Human, Pair 21 / metabolism
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Chromosomes, Human, Pair 8 / genetics
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Chromosomes, Human, Pair 8 / metabolism
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Core Binding Factor Alpha 2 Subunit / biosynthesis*
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Core Binding Factor Alpha 2 Subunit / genetics
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Humans
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K562 Cells
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism*
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Mice
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Nocodazole / pharmacology
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Oncogene Proteins, Fusion / biosynthesis*
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Oncogene Proteins, Fusion / genetics
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Protein Kinases / biosynthesis*
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Protein Kinases / genetics
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Protein Serine-Threonine Kinases
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RUNX1 Translocation Partner 1 Protein
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Translocation, Genetic
Substances
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AML1-ETO fusion protein, human
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Antineoplastic Agents
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Bub1b protein, mouse
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Cell Cycle Proteins
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Core Binding Factor Alpha 2 Subunit
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Oncogene Proteins, Fusion
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RUNX1 Translocation Partner 1 Protein
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SPAG5 protein, human
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Protein Kinases
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BUB1 protein, human
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Bub1 spindle checkpoint protein
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Protein Serine-Threonine Kinases
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Nocodazole