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, 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, Cell Press; 1994.
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