1 / 20

E2A – bHLH transcription factor-fusion proteins in Leukemia

E2A – bHLH transcription factor-fusion proteins in Leukemia. Sarah Woznicki 3-18-03. E2A Gene. TCF3 (Transcription Factor 3) ITF1 Immunoglobulin Enhancer Binding Location – chromosome 19 19p13.3. E Protein Family. E2A protein – part of family of E proteins

salvador-spencer
Download Presentation

E2A – bHLH transcription factor-fusion proteins in Leukemia

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. E2A – bHLH transcription factor-fusion proteins in Leukemia Sarah Woznicki 3-18-03

  2. E2A Gene • TCF3 (Transcription Factor 3) • ITF1 Immunoglobulin Enhancer Binding Location – chromosome 19 19p13.3

  3. E Protein Family • E2A protein – part of family of E proteins • Includes HEB and E2-2 proteins • E proteins are part of the basic helix-loop-helix (bHLH) family of DNA-binding transcription factors • Conserved helix-loop-helix (HLH) domain – imparts dimerization capabilities between HLH members • Conserved basic region – amino to HLH; allows HLH dimers to bind to DNA

  4. E Protein Family • Mammalian E proteins also share 2 conserved transcriptional activation domains • AD1 domain • Loop-helix (LH) domain

  5. E Protein Family • Class I HLH proteins • First identified based on their ability (as homo-, heterodimers) to bind with high affinity to DNA sequence – C-A-N-N-T-G – the E box site • E box sites present broadly in the genome

  6. E2A Gene • Encodes 2 E proteins • E12 • E47 • Arise through differential splicing of the exon encoding for the HLH domain

  7. E2A – function in normal cells • Transcription regulation • Heterdimerizes with tissue-specific bHLH proteins • Essential for normal B-cell hematopoiesis

  8. E2A – Role in Myogenesis • 3 stages of myogenesis- development of skeletal muscle cells • 1- determination of precursor myoblasts • 2- proliferation (and possible migration) of these precursor muscle cells • 3- differentiation into mature muscle • 4 genes – signal conversion of cell lines into muscle cells- myoD, myogenin, myf5, mrf4 • Members of bHLH family

  9. E2A – Role in Myogenesis • E2A protein -when bound to one of these myogenic proteins- increases the myogenic protein’s affinity for DNA binding • The muscle regulatory protein- E2A heterodimer then works directly or with other transcription factors to regulate expression of muscle-specific proteins needed in development

  10. E2A – Role in Lymphocyte Development • Common lymphoid progenitor cell can develop into 3 distinct cell types • B lymphocytes • T lymphocytes • NK cells • During lineage commitment / maturation, B and T lymphocyte development defined at different stages by • rearrangement of antigen receptor genes • gain/loss of cell surface and intracellular proteins • responses to growth survival factors • Gene expression at these levels controlled by bHLH transcription factors

  11. E2A – Role in Lymphocyte Development • E box – found in promoter and enhancer regions of a wide variety of B and T lineage specific genes – to which E proteins can bind • E2A – works with other transcription factors to maintain expression of target genes that promote lymphocyte maturation appropriately at each stage of development • Experimental support • E2A deficiency – leads to complete lack of B lineage cells • Over-expression of E12 – sufficient to activate transcription of several B lineage- specific genes in non-lymphoid cells

  12. Function of E2A at developmental stages • B-cell development • Commitment • IgH gene rearrangement • Proliferation/ survival • IgL gene rearrangement • Isotype switching • T-cell development • Works in similar mechanisms to promote stage progression

  13. E2A proteins and Leukemia • Implicated in cellular proliferation and apoptosis • 2 influences supported by current models • E2A acts as a tumor suppressor • Promoting B cell differentiation • Inhibiting cell cycle progression • Promoting apoptosis • Suggest that mutations in E2A gene inhibit normal E2A activity and lead to abnormal proliferation/ survival of early B cells – resulting in ALL • Paradoxically, ectopic expression of E2A mutants shown to decrease proliferation/ survival of early B cells

  14. E2A gene • E2A locus- target of 2 chromosomal translocations associated with human leukemia • Result in Gene Fusions • t (1; 19) (q23; p13) – E2A transactivating domains join to DNA binding domain of PBX1 homeodomain protein • t (17; 19) (q22; p13) – E2A transactivating domains join to bZIP domain of hepatic leukemic factor (HLF) • These gene fusions alter the action of proteins that normally function in the control of of growth and differentiation during hematopoiesis • Changes in control in this highly regulated process can result in blockades that permit accumulation of immature proliferating cells

  15. Gene Fusion Proteins - Translocations

  16. E2A- PBX1 fusion gene • Present in 25% of pre-B ALL cases • Induces T-cell lymphomas in transgenic mice • Binding of both PBX1 and E2A-PBX1 to consensus PBX1 DNA sequence stimulated by direct interactions between PBX1 and other HOX proteins • HOX proteins appear to direct E2A-PBX1 to DNA sites recognized by HOX: PBX1 complexes- therefore, likely that E2A-PBX1 interferes with hematopoietic differentiation by disrupting gene expression that is normally regulated by HOX proteins (apoptosis)

  17. E2A- PBX1 • Also works by reducing the number of copies and, therefore expression of E2A gene

More Related