Transcript E2A and pre-B cell acute lymphoblastic leukemias (ALL)

E2A and acute
lymphoblastic
leukemias (ALL)
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
What are the E2A proteins?
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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
Mouse Models...
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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
What about E2A +/- mice?
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Have half as many B-cells as wild-type
embryos
Suggests levels of E2A expression in cell
translates into levels of B-cells!
Roles of E2A in B-cell Differentiation:
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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
E2A plays a similar role in T-cell
development...
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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)
E2A’s role in Leukemia formation
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Chromosomal translocation t(1:19) 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
Two things to consider:
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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
E2A as a tumor suppressor...
Displacement of section of PBX1 by
the activator domains of E2A could...
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Increase PBX1 ability to activate
transcription
E2A-PBX1 localized to the nucleus
Affect the ability of inhibitor proteins to bind
to PBX1
Downstream Targets
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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
Acute Lymphoblastic Leukemia
(ALL)
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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
Treatment Options
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Chemotherapy
Hematopoietic Stem Cell Transplant for
high-risk cases
Current Research
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Optimize dosage and scheduling of
antileukemic agents based on patient’s
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
References
St. Jude Children’s 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):405414.
Schebesta, Michael et al. 2002. Transcriptional control of B-cell development.
Current Opinion in Immunology 14: 216-223.
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