Transcript Document 269395

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
 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 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 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 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
 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 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 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 protein
 Deregulated association of
E2A activation domains
(with cofactors) promotes
uncontrolled cell division
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 (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
 Aspland, S. E., H. H. Bendall, and C. Murre. “The Role of
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E2A-PBX1 in leukemogenesis.” Oncogene, Vol. 20, 57085717. Nature Publishing Group; 2001.
Zhuang,Y., P. Soriano, and H. Wintraub. “The Helix-LoopHelix 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_lymphoblas
tic_leukemia/printable&=yes....html