E2AbHLH fusion proteins in leukemia

Ginger Price

A basic helix-loop-helix (bHLH) transcription factor

These domains are essential for protein dimerization and DNA binding

What does E2A encode?

http://gibk26.bse.kyutech.ac.jp/jouhou/image/dna-protein/all/small_N1a0a.gif

E2A encodes several transcription factors via alternative splicing of precursor mRNA.

Multiple Protein Products

http://www.ncbi.nlm.nih.gov/Class/MLACourse/Modules/MolBioReview/alternative_splicing.html

E2A null mice are viable and fertile!

To find E2A function...

http://www.tla1.com/Talent/Lisa_Horstman/LH%20mice.JPG

Why are E2A proteins needed?

http://www.tmd.ac.jp/med/mbch/en_images/B%20cell%20develpment.jpg

Transcriptional Control of B cell Development

http://www-biology.ucsd.edu/labs/murre/NewFiles/research.html

Lack of Mature B cells

http://en.wikipedia.org/wiki/Image:Illu_blood_cell_lineage.jpg

Translocations that cause oncogenic E2A fusion proteins

http://www-biology.ucsd.edu/labs/murre/NewFiles/research.html

T(1;19)(q23;p13)

T(17;19)(q21-22;p23)

E2A-HLF fusion protein prevents apoptosis of defective cells

http://www.nature.com/onc/journal/v26/n47/fig_tab/1210766f3.html

E2A-PBX1 fusion protein structure

Hunger S P. Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis. Blood. 1996;87:1211–1224.

Estimated◦ New cases: 44, 270◦ Deaths: 21,710

Leukemia

http://www.adventisthealthcare.com/imgs/WAH/misc/2005CancerFrequency-500.gif

What are lymphocytes?

http://en.wikipedia.org/wiki/Image:SEM_Lymphocyte.jpg

Large: NK cells

Small: T cellsB cells

Most common cancer in children 1/29,000 each year

Acute Lymphoblastic Leukemia (ALL)

http://en.wikipedia.org/wiki/Image:ALL_-_Peripherial_Blood_-_Diagnosis_-_01.jpg

Chemotherapy

85% - 5 years or more

Treatment & Survival

Altura, Rachel A., Takeshi Inukai, Richard A. Ashmun, Gerard P. Zambetti, Martine F. Roussel, and A. Thomas Look The Chimeric E2A-HLF Transcription Factor Abrogates p53-Induced Apoptosis in Myeloid Leukemia Cells. Blood 92: 1397-1405

Bhalla, Savita, Spaulding, Christina, Brumbaugh, Rachel L., Zagort, Derek E., Massari, Mark E., Murre, Cornelis, Kee, Barbara L. Differential Roles for the E2A Activation Domains in B Lymphocytes and Macrophages. J Immunol 2008 180: 1694-1703

Ferramdo AA, Look AT (2005). Hematology, In: Hoffman (ed). Pathobiology of Acute Lymphoblastic Leukemia, 4th edn, chapter 63. http://www.nature.com/onc/journal/v26/n47/fig_tab/1210766f3.html

Herblot, Sabine, Aplan, Peter D., Hoang, Trang. Gradient of E2A Activity in B-Cell Development. Mol. Cell. Biol. 2002 22: 886-900

Hunger S P. Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis. Blood. 1996;87:1211–1224.

Hunger SP, Sun T, Boswell AF, Carroll AJ, McGavran L. Hyperdiploidy and E2A-PBX1 fusion in an adult with t(1;19)+ acute lymphoblastic leukemia: case report and review of the literature. Genes Chromosomes Cancer. 1997 Dec;20(4):392-8.

Kamps, M P, Look, A T, Baltimore, D. The human t(1;19) translocation in pre-B ALL produces multiple nuclear E2A-Pbx1 fusion proteins with differing transforming potentials. Genes Dev. 1991 5: 358-368

Lietz, Andreas , Martin Janz, Mikael Sigvardsson, Franziska Jundt, Bernd Dörken, Stephan Mathas (2007) Loss of bHLH transcription factor E2A activity in primary effusion lymphoma confers resistance to apoptosis . British Journal of Haematology 137 (4) , 342–348

Murre Lab Web Site. University of California at San Diego. http://www-biology.ucsd.edu/labs/murre/NewFiles/research.html

Sykes, David B., Kamps, Mark P. E2a/Pbx1 Induces the Rapid Proliferation of Stem Cell Factor-Dependent Murine Pro-T Cells That Cause Acute T-Lymphoid or Myeloid Leukemias in Mice. Mol. Cell. Biol. 2004 24: 1256-1269

Wikstrom, Ingela, Forssell, Johan, Goncalves, Mario, Colucci, Francesco, Holmberg, Dan. E2-2 Regulates the Expansion of Pro-B Cells and Follicular versus Marginal Zone Decisions. J Immunol 2006 177: 6723-6729

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