Download MYC and Burkitt Lymphoma

Burkitt lymphoma and
myelocytomatosis protooncogene (MYC)
Deeter Neumann
History of Burkitt Lymphoma
1887 Sir Albert Cook
Reports of mass in jaw
area
1934 Smith and Elmes
“Lymphoma
belt”
“round cell sarcomas”
1953 Capponi
ovary lymphosarcoma in
Cameroon children
1958 Dr. Burkitt
Denis Burkitt
Specific clinical syndrome
http://www.canceruptodate.blogspot.com/
Burkitt Lymphoma
B cell lymphoma
Most common form of tumor found in
African children
3 Subtypes
Endemic
Sporadic
Immunodeficiency-associated
“Starry Sky” histology
Tumor
http://commons.wikimedia.org/wiki/File:Burkitt%27s_
lymphoma.jpg
http://www.radiology.casereports.net/index.php/rcr/article/viewArticle/1
79/486
MYC positioned on Chromosome 8
Located at 8q24.21
Encodes a nuclear
phosphoprotein
Regulates
cell proliferation
differentiation
apoptosis
http://www.genecards.org/cgi-bin/carddisp.pl?gene=Myc
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-cells
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.section.148&ref=sidebar
http://science.kukuchew.com/tag/immunoglobulin/
MYC Protein
MYC_N
454 amino acids
HLH
MYC-LZ
MYC_N amino-terminal
HLH helix-loop-helix
MYC-MAX
MYC-LZ leucine zipper dimerization domain
http://www.ncbi.nlm.nih.gov/homologene/31092?ordinalpos=1&itool=EntrezSystem2.PEntrez.Homologene.Homologene
_ResultsPanel.Homologene_RVDocSum
Gene Ontology
http://www.ebi.ac.uk/QuickGO/GProtein?ac=P01106
MYC tag
MYC 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
Homo sapien
Rattus norvegicus
Mus musculus
Drosophila melanogaster
Pan troglodytes
Danio rerio
Canis lupus familiaris
Bos taurus
mRNA sequences were used to create
phylogram using clustalW
https://www.dpchallenge.com/image.php?IMAGE_ID=523504
DNA Motifs
7 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
http://string.embl.de
MM-1 (PFDN5)
Mouse Protein Network
MM-1
http://string.embl.de
Fly Protein Network
http://string.embl.de
Fly and Mouse Models
Human protein
Mouse protein
Fly protein
Rat protein
http://www.ncbi.nlm.nih.gov/homologene/31092?ordinalpos=1&itool=EntrezSystem2.PEntre
z.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 dMnt
dMnt major regulatory role at dMyc target
genes
dMnt function limits cell growth
Loss of dMyc affects protein synthesis
ribosome
http://media.photobucket.com/image/ribosome/bmahfood/Blog%20Photos/ribosome1.jpg
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
WT spleen
IgH-3’E-myc spleen
Lymph node
Spleen
IgH-3’E-myc spleen
http://www.jbc.org/cgi/content/full/280/13/12766
Lymphoma in lung
Lymphoma in kidney
Mouse Model for Burkitt Lymphoma
Homo Het
B cell
http://www.biooncology.com/bioonc/res
earch/b-cellbiology/index.m
http://www.informatics.jax.org/javawi2/servl
et/WIFetch?page=alleleDetail&key=39047
Future Directions
Understand 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-4C5RFFBJ&_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-4RFJ4N11&_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&f
ulltext=Sp1&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT
Questions?