Involvement of ID4 (Inhibitor of DNA Binding 4) in Haematopoietic Malignancies.pdf (4.03 MB)
Download file

Involvement of ID4 (Inhibitor of DNA Binding 4) in Haematopoietic Malignancies

Download (4.03 MB)
thesis
posted on 08.07.2011, 13:01 by Palminder Kaur Dusanjh
Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus have been described in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). One of these, t (6;14)(p22;q32), involved the Inhibitor of DNA Binding 4 (ID4) gene, resulting in deregulated ID4 expression. Members of the ID family are helix-loop-helix proteins that lack DNA binding domains. They are thought to regulate cellular differentiation and proliferation by binding and sequestering E proteins from their DNA targets. The aim of this thesis was to examine the expression and oncogenic potential of ID4 in B-cells. ID4 expression was detected in a subset of chronic lymphocytic leukaemia (CLL) and BCP-ALL lacking the ID4/IGH chromosomal translocation. ID4 expression defined a subtype of BCP-ALL with a distinctive gene signature. ID4, unlike other members of the ID family is not expressed in normal B-cells. Unexpectedly, ectopic ID4 protein expression in most but not all derived B-cell lines reduced proliferation and induced cell cycle arrest. B-cells in ID4-induced cell cycle arrest showed a partial resistance to apoptosis. Proteomic analysis of cell lines expressing ectopic ID4 showed that ID4 interacted with E proteins, although these data could not be confirmed with endogenous ID4 for technical reasons. Primary normal mouse B lymphocyte progenitors showed impaired B-cell development in an in vitro assay following expression of ID4. In contrast, ID4 cooperated with myc over-expression in inducing proliferation of murine B lymphocyte progenitors. Collectively, these data suggest that ID4 may be a novel genetic “driver” in different subtypes of B-cell malignancy. ID4 may contribute to leukemogenesis of B-cell progenitors by inducing inappropriate gene expression and affecting mitosis. This collectively promotes genetic instability and generates a preleukemic stage.

History

Supervisor(s)

Dyer, Martin; Karran, Elizabeth

Date of award

01/06/2011

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en

Usage metrics

Categories

Keywords

Exports