title: A leukemia fusion protein attenuates the spindle checkpoint and promotes aneuploidy.
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.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Boyapati
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Luke F
authors.initials: LF
authors.lastname: Peterson
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Biggs
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D000782:Aneuploidy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000378:metabolism; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015739:Nocodazole / Q000494:pharmacology; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D000075142:RUNX1 Translocation Partner 1 Protein; D014178:Translocation, Genetic
chemical_list: C107844:AML1-ETO fusion protein, human; D000970:Antineoplastic Agents; C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C486663:SPAG5 protein, human; D011494:Protein Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D015739:Nocodazole