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E2A: master regulator of B-cell lymphopoiesis

E2A: master regulator of B-cell lymphopoiesis. Sun Hee Kim. hematopoiesis. E2A is a transcription factor. Encodes E12 and E47: immunoglobulin enhancer-binding proteins in B cells; bind to E box motifs in Ig promoter and enhancer elements Nuclear location

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E2A: master regulator of B-cell lymphopoiesis

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  1. E2A: master regulator of B-cell lymphopoiesis Sun Hee Kim

  2. hematopoiesis

  3. E2A is a transcription factor • Encodes E12 and E47: immunoglobulin enhancer-binding proteins in B cells; bind to E box motifs in Ig promoter and enhancer elements • Nuclear location • 2 transcriptional activation domains in the NH2-terminal • 1 basic helix-loop-helix (bHLH) domain in the C-terminal

  4. E2A functions in B cell differentiation • E2A knockout mice: generate mouse embryonic stem cell lines homozygous for E2A deletion and differentiate them in tissue culture or subcutaneous of the mouse

  5. E2A functions in B cell differentiation • Results: E2A -/- offspring experienced post-natal death suggesting that E2A mutation does not affect embryonic development • E2A is not essential for muscle, cartilage, nerve, and erythroid cell lineage formations  genetic redundancy (E2-2/HEB)

  6. E2A functions in B cell differentiation • B cell differentiation is blocked at its earliest stage in E2A -/-, while T cell, macrophage, granulocyte, and erythroid lineages seem normal • E2A +/- heterozygotes have about half as many B cells

  7. E2A-PBX1: oncogenic fusion protein • The t(1;19) fusion event combines the activation domains of E2A with the DNA binding homeodomain region of another protein: PBX1

  8. E2A-PBX1: oncogenic fusion protein • E2A-PBX1 activates expression of HOX/PBX1 target genes • PBX1 inhibits activity of HOX proteins • HOX genes are oncogenic when over-expressed or become part of chimeras containing activation domains

  9. E2A-PBX1: oncogenic fusion protein • E2A-PBX1 binds to a subset of the sites bound by PBX1; it is limited and cannot bind to everything that PBX1 is able to bind to

  10. E2A-PBX1: oncogenic fusion protein • Deregulated association of E2A activation domains (with cofactors) promotes uncontrolled cell division

  11. Acute Lymphoblastic Leukemia (ALL) • Leukemia is cancer of the white blood cells; overproliferation of immature white blood cells • Chromosomal translocation t(1;19) is detected in approximately 23% of all pediatric pre-B cell ALL cases • ALL is most common in childhood (4-5 years old); childhood ALL has a better survival rate than adult ALL • ALL crowds out the normal cells in bone marrow and spreads to other organs

  12. Acute Lymphoblastic Leukemia (ALL) • ‘Acute’ refers to the undifferentiated/immature state of circulating lymphocytes (‘blasts’) and the rapid progression of the disease (fatal in weeks to months if untreated) • Symptoms include weakness, fatigue, anemia, frequent infections, weight loss, bruising, breathlessness • Diagnosed by a high white blood cell count and blasts cells seen on blood smear, and a bone marrow biopsy • Treatment: chemotherapy/radiation therapy

  13. References • Aspland, S. E., H. H. Bendall, and C. Murre. “The Role of E2A-PBX1 in leukemogenesis.” Oncogene, Vol. 20, 5708-5717. Nature Publishing Group; 2001. • Zhuang, Y., P. Soriano, and H. Wintraub. “The Helix-Loop-Helix Gene E2A Is Required for B Cell Formation.” Cell, Vol. 79, 875-884. Cell Press; 1994. • http://atlasgeneticsoncology.org/genes/e2a.html • http://www.ihop-net.org/unipub/iHOP/gs/125393.html • http://pubmed.com/w/index.php?title=Acute_lymphoblastic_leukemia/printable&=yes....html

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