E2a and its role in pre b cell all
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E2A and its Role in pre-B cell ALL. Allison Person 3-16-04. Acute Lymphoblastic Leukemia (ALL). Lymphocytes affected Bone marrow makes too many lymphocytes that do not mature correctly Crowding out of other normal blood cells Immature lymphocytes do not fight infection properly.

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E2A and its Role in pre-B cell ALL

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E2a and its role in pre b cell all

E2A and its Role in pre-B cell ALL

Allison Person

3-16-04


Acute lymphoblastic leukemia all

Acute Lymphoblastic Leukemia (ALL)

  • Lymphocytes affected

  • Bone marrow makes too many lymphocytes that do not mature correctly

    • Crowding out of other normal blood cells

    • Immature lymphocytes do not fight infection properly

health.allrefer.com


Pre b cell all

Pre-B cell ALL

  • Overproliferation of pre-B cells

  • B cell = WBC that produces antibodies

  • Pre-B cell = early stage B cell

Biol 169 lecture notes, Spring 2004


E2a and its role in pre b cell all

E2A

  • Transcription factor

  • E2A binding detected at the promoters and enhancers of several essential B-lineage genes

    • VpreB light chain promoter

    • EBF promoter

    • Mb-1 promoter


E2a binds to dna

E2A Binds to DNA

  • E2A binds to DNA as a homodimeric complex

Aspland et al.


E2a is a bhlh protein

E2A is a bHLH protein

  • bHLH = basic helix-loop-helix

Cooper et al.


The normal function of e2a

The Normal Function of E2A

  • Role in directing B cell lineage commitment

  • Also plays multiple roles at later stages of B cell development and maturation

Schebesta et al.


E2a deficient mice

E2A Deficient Mice

  • Heterozygous embryos contain ~ ½ as many B cells as wildtype embryos

  • Homozygous mutant mice

    • Develop full term w/o apparent abnormalities

    • High rate of postnatal death

    • Retarded postnatal growth

    • Contain no B cells

http://compdiag.molgen.mpg.de/docs/


The fusion of e2a with pbx1

The Fusion of E2A with PBX1

  • t(1;19) translocation

  • Detected in ~23% of all pediatric pre-B cell ALL cases

  • Activation domains of E2A + homeodomain (HD) regions of PBX1


The translocation

The Translocation

Aspland et al.


The fusion has 2 primary effects

The Fusion has 2 Primary Effects

  • Disrupts one allele of both E2A and PBX1

    • Reduction in levels of wildtype E2A

  • Generation of novel fusion gene, E2A-PBX1, expressed under the control of E2A regulatory sequences


What does the fusion gene do

What does the fusion gene do?

  • Association of Hox proteins with E2A-PBX1 activates transcription of many Hox/PBX1 target genes

Aspland et al.


The targets

The Targets

  • There are several targets

  • Wnt16

    • Encodes a growth factor

    • Normally expressed in spleen, appendix, and lymph nodes

    • High levels expressed in bone marrow of pre-B cell ALL patients carrying E2A-PBX1 hybrid gene

McWhirter et al.


E2a pbx1 constitutively activates wnt16

E2A-PBX1 Constitutively Activates Wnt16

  • Members of PBX1 family normally repress Wnt16 transcription in pre-B lymphocytes

  • Fusion of E2A with PBX1 activates Wnt16

    • Aberrant proliferation and/or survival of pre-B lineage cells


Secondary mutations

Secondary Mutations

  • Pim1 and Notch1

  • Mice engineered to express:

    • E2A-PBX1 and either mutated Pim1 or Notch1

    • E2A-PBX1 alone


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