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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E2A: master regulator of B-cell lymphopoiesis

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E2a master regulator of b cell lymphopoiesis

E2A: master regulator of B-cell lymphopoiesis

Sun Hee Kim


Hematopoiesis

hematopoiesis


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


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