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The characterisation of a functional interaction between Ikaros and Foxp1 in pre-B-cells and acute lymphoblastic leukaemia

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Title: The characterisation of a functional interaction between Ikaros and Foxp1 in pre-B-cells and acute lymphoblastic leukaemia
Authors: Bond, Jonathan
Item Type: Thesis or dissertation
Abstract: B-lymphopoiesis is characterised by orderly progression through a series of stages of differentiation, each of which is associated with specific patterns of protein expression and cellular proliferation. These processes require a high degree of regulation by the coordinated action of a series of transcription factors that are critical for appropriate stage-specific gene expression. We describe a novel interaction between Ikaros and Foxp1, two transcription factors that are essential for normal B-lymphopoiesis, and which frequently exhibit abnormal expression in B-lymphoid malignancy. By co-immunoprecipitation, we have demonstrated physical association between the DNA-binding domains of these proteins in vivo, which is recapitulated in a cell-free system in vitro. In functional experiments, ectopic overexpression of Foxp1 by retroviral infection of pre-B-cells resulted in an increased proportion of cells in the G2 phase of the cell cycle. This phenotype was associated with increased transcription of Gpr132, a gene which encodes the G2A protein that is known to induce G2/M cell cycle arrest in mammalian cells. The phenotypic effects of Foxp1 overexpression were abolished by coinfection with Ikaros, which abrogated induction of Gpr132 expression by Foxp1, and caused displacement of Foxp1 from the Gpr132 gene, as shown by chromatin immunoprecipitation. Co-infection of IK6 (an Ikaros isoform which lacks the Foxp1 interaction domain and which is frequently expressed in B-cell acute lymphoblastic leukaemia) had no effect on Gpr132 expression or Foxp1 occupancy of the Gpr132 gene, and failed to abolish the phenotypic effects of Foxp1 overexpression. Our results contribute to a growing understanding of transcription factor interplay during normal lymphopoiesis, and provide mechanistic insights into the roles of Ikaros and Foxp1 in lymphocyte cell cycle homeostasis. In addition, these findings may contribute to the understanding of cell cycle dysregulation and chemotherapeutic resistance that characterise certain subtypes of acute leukaemia that exhibit aberrant expression of these proteins.
Content Version: Open Access
Issue Date: Apr-2013
Date Awarded: Jul-2013
URI: http://hdl.handle.net/10044/1/14428
DOI: https://doi.org/10.25560/14428
Supervisor: Dillon, Niall
Department: Institute of Clinical Science
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Department of Clinical Sciences PhD Theses



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