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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

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E2A – bHLH transcription factor-fusion proteins in Leukemia

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  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

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