Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-Transgenic mice

Chen, E., Lim, M.S., Rosic-Kablar, S., Liu, J., Jolicoeur, P., Dube, I.D. and Hough, M.R. 2006. Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-Transgenic mice. Oncogene. 25, pp. 2575-2587. https://doi.org/10.1038/sj.onc.1209285

TitleDysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-Transgenic mice
TypeJournal article
AuthorsChen, E., Lim, M.S., Rosic-Kablar, S., Liu, J., Jolicoeur, P., Dube, I.D. and Hough, M.R.
Abstract

Dysregulated expression of the homeobox gene, HOX11 is a frequent etiologic event in T-cell acute lymphoblastic leukemias. HOX11-transgenic mice (IgHμ-HOX11Tg)-expressing HOX11 in the B-cell compartment develop B-cell lymphomas with extended latency. The latency suggests that additional genetic events are required prior to the onset of malignant lymphoma. We report the identification of 17 HOX11 collaborating genes, revealed through their propensity to be targeted in a proviral insertional mutagenesis screen. Seven integrations disrupted genes in mitotic spindle checkpoint control, suggesting that cells with elevated HOX11 expression are especially sensitive to dysregulation of chromosome segregation during mitosis. IgHμ-HOX11Tg primary B-lymphocyte cultures exposed to the aneugenic agents, colchicine and colcemid, exhibited increased incidences of chromosome missegregation as assessed by cytokinesis-block micronucleus assays. Additionally, IgHμ-HOX11Tg cultures were shown to exhibit aberrant bypass of spindle checkpoint arrest, as assessed by the increased presence of cycling cells determined by assessment of DNA content and by BrdU immunolabelling. Western immunoblotting revealed elevated expression of the mitotic effector molecules, cyclin A, cyclin B1 and cdc20 in IgHμ-HOX11Tg cultures. Moreover, spontaneously arising lymphoid neoplasms in IgHμ-HOX11Tg mice frequently exhibit aberrant expression of mitotic regulators, concomitant with increased development of micronuclei, abnormal mitotic checkpoint control and increased incidences of abnormal karyotypes when expanded in culture. Collectively, these findings indicate that abnormal regulation of spindle checkpoint control as a result of HOX11 overexpression leads to a heightened predisposition for development of aneuploidy, contributing to oncogenesis.

JournalOncogene
Journal citation25, pp. 2575-2587
ISSN0950-9232
Year2006
PublisherNature Publishing Group
Digital Object Identifier (DOI)https://doi.org/10.1038/sj.onc.1209285
Publication dates
Published09 Jan 2006

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