E2A and Acute Lymphoblastic Leukemia (ALL)

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 ofantibody 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/actprograms/Health/cancer_connection/cutsforcancer/cancer_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 • Causes chimeric proteins • Fuse E2A with PBX1 or HLF Aspland SE, Bendall HH, Murre C: The role of E2A-PBX1 in leukemogenesis.Oncogene (2001)20, 5708-5717.

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/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/

19. Questions?