Burkitt lymphoma and myelocytomatosis proto-

oncogene (MYC)

Deeter Neumann

History of Burkitt Lymphoma

Denis Burkitt

1887 Sir Albert Cook

Reports of mass in jaw area

1934 Smith and Elmes

“round cell sarcomas”

1953 Capponi

ovary lymphosarcoma in Cameroon children

1958 Dr. Burkitt

Specific clinical syndrome

“Lymphoma belt”

http://www.canceruptodate.blogspot.com/

Burkitt LymphomaB cell lymphoma

Most common form of tumor found in African children

3 Subtypes Endemic

Sporadic

Immunodeficiency-associated

http://www.radiology.casereports.net/index.php/rcr/article/viewArticle/179/486

http://commons.wikimedia.org/wiki/File:Burkitt%27s_lymphoma.jpg

“Starry Sky” histology

Tumor

MYC positioned on Chromosome 8

Encodes a nuclear phosphoprotein

Regulates

cell proliferation

differentiation

apoptosis

http://www.genecards.org/cgi-bin/carddisp.pl?gene=Myc

Located at 8q24.21

http://ghr.nlm.nih.gov/handbook/illustrations/apoptosismacrophage

MYC’s role in Burkitt Lymphoma

Chromosomal translocation disrupting immunoglobin (Ig) genes

Ig locus control of MYC

Constitutive MYC expressed in B-cellshttp://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.section.148&ref=sidebar http://science.kukuchew.com/tag/immunoglobulin/

MYC Protein

MYC_N amino-terminal

HLH helix-loop-helix

MYC-LZ leucine zipper dimerization domainhttp://www.ncbi.nlm.nih.gov/homologene/31092?ordinalpos=1&itool=EntrezSystem2.PEntrez.Homologene.Homologene_ResultsPanel.Homologene_RVDocSum

MYC_N HLH MYC-LZ454 amino acids

MYC-MAX

Gene Ontology

http://www.ebi.ac.uk/QuickGO/GProtein?ac=P01106

MYC tagMYC is a small protein

Proteins lacking specific Antibodies (Ab)

Create recombinant protein

Identify the Protein using anti-MYC Abs

https://www.cellsignal.com/products/images/2276_fig3.jpg

MYC Phylogeny

mRNA sequences were used to create phylogram using clustalW

Pan troglodytes

Canis lupus familiaris

Homo sapien

Mus musculus

Danio rerio

Bos taurus

Rattus norvegicus

Drosophila melanogaster

https://www.dpchallenge.com/image.php?IMAGE_ID=523504

DNA Motifs7 DNA motifs found

Stimulating Protein 1 (Sp1)

Interest in Sp1

Protein found in humans

DNA-binding protein

Regulates “prosurvival proteins” and “prodeath proteins”

http://motif.genome.jp/

Human Protein Network

MAX

SMAD3

MM-1 (PFDN5) http://string.embl.de

Mouse Protein Network

MM-1

http://string.embl.de

Fly Protein Network

http://string.embl.de

Fly and Mouse Models

Human protein

Fly protein

Mouse protein

Rat proteinhttp://www.ncbi.nlm.nih.gov/homologene/31092?ordinalpos=1&itool=EntrezSystem2.PEntrez.Homologene.Homologene_ResultsPanel.Homologene_RVDocSum

Modeling MYC in Fly

Investigated roles of drosophilaMyc (dMyc) and Mnt

Null dMyc- effect on organismal and cellular growth

Created dm4 null mutant and dm4dmnt1 flies

dm4 vs. dm4dmnt1

dMyc vs dMntdMnt major regulatory role at dMyc target genes

dMnt function limits cell growth

Loss of dMyc affects protein synthesis

http://media.photobucket.com/image/ribosome/bmahfood/Blog%20Photos/ribosome1.jpg

ribosome

Knock-in Mice

Myctm1Lbox

Allele knock-in

IgH 3’ enhancer upstream of Myc locus

Created heterozygote and homozygote

http://www.jimmunol.org/cgi/content/full/179/9/6033#F1

WT vs. IgH-3’E-myc mouse

http://www.jbc.org/cgi/content/full/280/13/12766

Lymph node

Spleen

WT spleen IgH-3’E-myc spleen

Lymphoma in lung Lymphoma in kidney

IgH-3’E-myc spleen

Mouse Model for Burkitt Lymphoma

http://www.informatics.jax.org/javawi2/servlet/WIFetch?page=alleleDetail&key=39047

B cell

http://www.biooncology.com/bioonc/research/b-cellbiology/index.m

Homo Het

Future DirectionsUnderstand the cause of translocation

Gene therapy with MM-1 or Smad3 to supress tumorigenesis?

Microarrays to detect specific interactions of genes in both Burkitt patient and normal individual

Target other bHLH rescue proteins

Cell cycle progression in normal and Burkitt cells

Utilize rat as model organism!

???

https://eapbiofield.wikispaces.com/Chapter+12+Kendall

References

Boxer, LM., Wang, j. (2005). Regulatory elements in the immunoglobin heavy chain gene 3’-enhancers induce c-myc deregulation and lymphomagenesis in murine B cells. Journal of Biological Chemistry. 280(13). Retrieved from: http://www.jbc.org/cgi/content/full/280/13/12766

Burkitt, D. (1962). A Lymphoma Syndrome in African Children. Annals of the Royal College of Surgeons of England. 30(4):211-219. Retrieved from: http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=2414150&pageindex=9#page

Feng, X., Liang, Y., and Liang, M.(2002).Direct Interaction of c-Myc with Smad2 and Smad3 to Inhibit TGF-β-Mediated Induction of the CDK Inhibitor p15Ink4B. Molecular Cell. 9(1):133-143. Retrieved from: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSR-4C5RFFB-J&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=5ed8f5bd595b7103fdbe1b0aa055b850

Hagio, Y., Kimura, Y., and Taira, T. (2006) Distinct localizations and repression activities of MM-1 isoforms toward c-Myc. Journal of Biological Chemistry. 97(1):145-55.

Pierce, SB., Yost, C., and Andersen, S. (2008). Drosophila growth and development in absence of dMyc and dMnt. Developmental Biology. 315(2):303-316. Retrieved from: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WDG-4RFJ4N1-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=9b9a25effa5156ae728c4d67c7b2e772

Thorley-Lawson, DA., Allday, MJ. (2008). The Curious case of the tumor virus: 50 years of Burkitt Lymphoma. Nature Reviews. 6:913-922

Ryu, H., Lee, J., Zaman, K., Kubulis, J., Ferrante, R. J., Ross, B. D., Neve, R., Ratan, R. R. (2003). Sp1 and Sp3 are Oxidative Stress-Inducible, Antideath Transcriptional Factors in Cortical Neurons. The Journal of Neuroscience. 23(9):3597. Retrieved from:http://www.jneurosci.org/cgi/content/full/23/9/3597?maxtoshow=&HITS=&hits=&RESULTFORMAT=1&andorexacttitle=and&fulltext=Sp1&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT

Questions?