e2a and acute lymphoblastic leukemia (all) jeremy petree
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E2A and Acute Lymphoblastic Leukemia (ALL)
Jeremy Petree
E2A is a bHLH transcription factor
http://datf.cbi.pku.edu.cn/family_structure/bHLH_structure.php
Regulates B lymphocyte differentiation
Two proteins through differential splicingE12E47
Expressed in many cell types
Bind to E box motifs in immunoglobulin (Ig) promoters and enhancer
Regulate the Ig locus activation and B-cell development
B-Cell Lineage Commitment
In knockout mice B-cell development arrests at
early pro-B cell stage before heavy chain rearrangement
Thus needed at earliest stages in B-cell development
Also involved in late stage B-Cell development regulates lymphocyte specific
genes in non-lympmphatic tissue Murre C. ResearchInterests of the Murre Lab. http://www-
biology.ucsd.edu/labs/murre/NewFiles/research.html
Has a role in Ig class switching
Knockout mice also have T-cell defects
Pathway
E2A antagonized by Notch1 and Id2
Schebesta M, Heavey B, Busslinger M: Transcriptional cntrol of B-cell development. Current Opinion in Immunology (2002) 14, 216-223.
Ig Rearrangement
E2A regulates Rag1 and Rag2, which in turn regulate V(D)J joining ofantibody genes"
Cancer
E2A may act as a tumor suppressor Over expression of E47 prevents foci
development in NIH3T3 cells
Regulates expression of the CKI p21"
Null mutant mice develop thyomas within 75 days after birth
Heterozygosity in Mice
Lack of functional E2A to act as a tumor suppressor
Increase the population of undifferentiated progenitor cells
Acute Lymphoblastic Leukemia (ALL)
3,930 new cases each year
Usually affects children under 19
Frequency increases in older individuals
Malignant immature white blood cells
Blocks the production of normal bone marrow cells
Swiggum AJ: Current Cancer Research. Acting in the Community Together (2006) http://apps.carleton.edu/campus/act/actprograms/Health/cancer_connection/cutsforcancer/cancer_research/
Causes
Most cases result from spontaneous mutations
Exposure to radiation Development rate different in different
locations
Advances in treatment 85% survive past five years
Chromosomal Translocation
Aspland SE, Bendall HH, Murre C: The role of E2A-PBX1 in leukemogenesis. Oncogene (2001) 20, 5708-5717.
Causes chimeric proteinsFuse E2A with PBX1 or HLF
E2A-PBX1 homodimers may have a dominant negative effect
Aspland SE, Bendall HH, Murre C: The role of E2A-PBX1 in leukemogenesis. Oncogene (2001) 20, 5708-5717.
E2A-PBX1 Transgenic Mice
Lymphoid tumors by five months after birth
retroviral induced E2A-PBX1 transplanted bone marrow developed myeloid leukemia by five months after transfer
A second mutation (Pim1 Notch1) increase the rate of tumorigenesis
Sources
Acute Lymphoblastic Leukemia in Children: Fact Sheet. National Cancer Institute (2002) http://www.cancer.gov/newscenter/all3
Acute Lymphocytic Leukemia. The Leukemia and Lymphoma Society (2007) http://www.leukemia-lymphoma.org/all_page?item_id=7049
Aspland SE, Bendall HH, Murre C: The role of E2A-PBX1 in leukemogenesis. Oncogene (2001) 20, 5708-5717.
Murre C. ResearchInterests of the Murre Lab. http://www-biology.ucsd.edu/labs/murre/NewFiles/research.html
Schebesta M, Heavey B, Busslinger M: Transcriptional cntrol of B-cell development. Current Opinion in Immunology (2002) 14, 216-223.
Structure of bHLH Family. Database of Arabidopsis Transcription Factors (2006) http://datf.cbi.pku.edu.cn/family_structure/bHLH_structure.php
Swiggum AJ: Current Cancer Research. Acting in the Community Together (2006) http://apps.carleton.edu/campus/act/actprograms/Health/cancer_connection/cutsforcancer/cancer_research/
Questions?