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?