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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). 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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  1. E2A and its Role in pre-B cell ALL Allison Person 3-16-04

  2. 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

  3. 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

  4. 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

  5. E2A Binds to DNA • E2A binds to DNA as a homodimeric complex Aspland et al.

  6. E2A is a bHLH protein • bHLH = basic helix-loop-helix Cooper et al.

  7. 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.

  8. 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/

  9. 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

  10. The Translocation Aspland et al.

  11. 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

  12. What does the fusion gene do? • Association of Hox proteins with E2A-PBX1 activates transcription of many Hox/PBX1 target genes Aspland et al.

  13. 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.

  14. 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

  15. Secondary Mutations • Pim1 and Notch1 • Mice engineered to express: • E2A-PBX1 and either mutated Pim1 or Notch1 • E2A-PBX1 alone

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