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?
Top Related