e2a master regulator of b cell lymphopoiesis n.
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E2A: master regulator of B-cell lymphopoiesis

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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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Presentation Transcript
e2a is a transcription factor
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
e2a functions in b cell differentiation
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
e2a functions in b cell differentiation1
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)
e2a functions in b cell differentiation2
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
e2a pbx1 oncogenic fusion protein
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
e2a pbx1 oncogenic fusion protein1
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
e2a pbx1 oncogenic fusion protein2
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
e2a pbx1 oncogenic fusion protein3
E2A-PBX1: oncogenic fusion protein
  • Deregulated association of E2A activation domains (with cofactors) promotes uncontrolled cell division
acute lymphoblastic leukemia all
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
acute lymphoblastic leukemia all1
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
references
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