1. E2A and Acute Lymphoblastic Leukemia (ALL) Jeremy Petree

2. E2A is a bHLH transcription factor http://datf.cbi.pku.edu.cn/family_structure/bHLH_structure.php

3. Regulates B lymphocyte differentiation Two proteins through differential splicing E12 E47

4. 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

5. 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

6. Has a role in Ig class switching Knockout mice also have T-cell defects

7. 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.

8. Ig Rearrangement E2A regulates Rag1 and Rag2, which in turn regulate V(D)J joining of antibody genes"

9. 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

10. Heterozygosity in Mice Lack of functional E2A to act as a tumor suppressor Increase the population of undifferentiated progenitor cells

11. 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/actprogram s/Health/cancer_connection/cutsforcancer/cance r_research/

12. Causes Most cases result from spontaneous mutations Exposure to radiation Development rate different in different locations

13. Advances in treatment 85% survive past five years

14. Chromosomal Translocation Aspland SE, Bendall HH, Murre C: The role of E2A-PBX1 in leukemogenesis. Oncogene (2001) 20, 5708-5717. Causes chimeric proteins Fuse E2A with PBX1 or HLF

15. 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.

16. 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

17. A second mutation (Pim1 Notch1) increase the rate of tumorigenesis

18. Sources Acute Lymphoblastic Leukemia in Children: Fact Sheet. National Cancer Institute (2002) http://www.cancer.gov/newscenter/all3http://www.cancer.gov/newscenter/all3 Acute Lymphocytic Leukemia. The Leukemia and Lymphoma Society (2007) http://www.leukemia-lymphoma.org/all_page?item_id=7049 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.phphttp://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/

19. Questions?