E2A and acute lymphoblastic leukemias (ALL)

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E2A and acute lymphoblastic leukemias (ALL)
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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

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E2A
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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

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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

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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!

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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

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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)

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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

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E2A as a tumor suppressor...
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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

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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

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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

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Treatment Options

• Chemotherapy
• Hematopoietic Stem Cell Transplant for high-risk
  cases

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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

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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