1 / 13

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

saxon
Télécharger la présentation

E2A: master regulator of B-cell lymphopoiesis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related