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
thesisposted on 2011-07-08, 13:01 authored 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.