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E2A and acute lymphoblastic leukemias (ALL)

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Title: E2A and acute lymphoblastic leukemias (ALL)


1
E2A and acute lymphoblastic leukemias (ALL)
2
A closer look at the E2A gene...
  • Other names TCF3, ITF1, and Factors E12/E47
  • Located on chromosome 19
  • Encodes two proteins E12 and E47
  • 17 exons

3
E2A
4
What are the E2A proteins?
  • Transcription factors
  • Members of the basic helix-loop-helix (bHLH)
    superfamily
  • Necessary for forming protein dimers and making
    contact with DNA
  • Bind to consensus E-box sequence sites

5
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Mouse Models...
  • E2A -/- mutants develop to full term without
    apparent abnormalities
  • High rate of postnatal death
  • Show retarded postnatal growth
  • Contain no B cells while T-cell, macrophage,
    granulocyte, and erythroid lineages are intact

7
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8
What about E2A /- mice?
  • Have half as many B-cells as wild-type embryos
  • Suggests levels of E2A expression in cell
    translates into levels of B-cells!

9
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11
Roles of E2A in B-cell Differentiation
  • Induces expression of other lineage-specific
    transcription factors (including EBF and RAG
    proteins)
  • Collaborates with EBF to regulate expression of
    other B-lineage genes
  • Regulates immunoglobulin gene recombination by
    facilitating access of RAG recombinase to
    recombination loci

12
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13
E2A plays a similar role in T-cell development...
  • E2A-HEB heterodimers contribute to the regulation
    of CD4 expression
  • Plays important roles in recombination of T-cell
    receptor
  • Provides survival signal for immature T-cells
  • Proposed to also have many negative affects on
    T-cell development (not well understood)

14
E2As role in Leukemia formation
  • Chromosomal translocation t(119) creates a
    fusion protein E2A-PBX1
  • Fusion protein combines the activator domains of
    E2A with the DNA-binding homeodomain region of
    PBX1
  • Fusion protein retains ability to interact with
    HOX proteins to activate transcription

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Two things to consider
  • The effect of E2A heterozygosity on tumor
    development( especially considering E2A as a
    tumor suppressor)
  • The E2A-PBX1 fusion protein novel biochemical
    properties and functional activities

17
E2A as a tumor suppressor...
18
Displacement of section of PBX1 by the activator
domains of E2A could...
  • Increase PBX1 ability to activate transcription
  • E2A-PBX1 localized to the nucleus
  • Affect the ability of inhibitor proteins to bind
    to PBX1

19
Downstream Targets
  • EB-1 encodes a phosphotyrosine-binding domain
    protein, and as such may have a role in the
    regulation of cell proliferation
  • Wnt16 encodes a member of the WNT/WG family of
    growth factors members of this family have been
    identified as potent activators of growth and
    differentiation

20
Acute Lymphoblastic Leukemia (ALL)
  • Most common form of childhood cancer
  • Undifferentiated lymphoid cells accumulate in
    bone marrow, replace normal blood cells, and
    spread to other parts of the body
  • 3,000 children are diagnosed each year
  • Peak incidence from 3-5 years of age
  • 98-99 of children diagnosed early attain initial
    complete remissions
  • Approximately 80 of patients can be cured

21
Treatment Options
  • Chemotherapy
  • Hematopoietic Stem Cell Transplant for high-risk
    cases

22
Current Research
  • Optimize dosage and scheduling of antileukemic
    agents based on patients leukemic cell genetic
    features
  • Microarray technology to obtain a profile of gene
    and protein expression in leukemia cells
  • Safety of stem cell transplant and increase the
    number of donors

23
References
  • St. Jude Childrens Research Hospital Acute
    Lymphoblastic Leukemia
  • http//www.stjude.org/diseasesummaries/0,2557,449
    _2165_2987,00.html
  • Atlas of Genetics and Cytogenetics in Oncology
    and Hematology
  • http//www.infobiogen.fr/services/chromcancer/
    Genes/E2A.html
  • Cooper, G.M. The Cell A molecular approach
  • http//www.ncbi.nlm.nih.gov/books/bv.fcgi?rid
    cooper.figgrp.837
  • Aspland, S.E. et al. 2001. The role of E2A-PBX1
    in leukemogenesis. Oncogene 20 5708-5717.
  • Zhuang, Yuan et al. 1994. The helixl-loop-helix
    gene E2A is required for B cell formation. Cell
    79 875-884.
  • Greenbaum, Stephen and Yuan Zhuang. 2002.
    Regulation of early lymphocyte development by E2A
    family proteins. Seminars in Immunology
    14(6)405-414.
  • Schebesta, Michael et al. 2002. Transcriptional
    control of B-cell development. Current Opinion in
    Immunology 14 216-223.
  • http//www.cella.cn/book/13/images/image021.jpg
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