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”

Burkitt Lymphoma B cell lymphoma Most common form of tumor found in African children 3 Subtypes Endemic Sporadic Immunodeficiency-associated 79/486 lymphoma.jpg “Starry Sky” histology Tumor

MYC positioned on Chromosome 8 Encodes a nuclear phosphoprotein Regulates cell proliferation differentiation apoptosis Located at 8q

MYC’s role in Burkitt Lymphoma Chromosomal translocation disrupting immunoglobin (Ig) genes Ig locus control of MYC Constitutive MYC expressed in B-cells

MYC Protein MYC_N amino-terminal HLH helix-loop-helix MYC-LZ leucine zipper dimerization domain _ResultsPanel.Homologene_RVDocSum MYC_NHLHMYC-LZ 454 amino acids MYC-MAX

Gene Ontology

MYC tag MYC is a small protein Proteins lacking specific Antibodies (Ab) Create recombinant protein Identify the Protein using anti-MYC Abs

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

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”

Human Protein Network MAX SMAD3 MM-1 (PFDN5)

Mouse Protein Network MM-1

Fly Protein Network

Fly and Mouse Models Human protein Fly protein Mouse protein Rat protein 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 dm 4 null mutant and dm 4 dmnt 1 flies

dm 4 vs. dm 4 dmnt 1

dMyc vs dMnt dMnt major regulatory role at dMyc target genes dMnt function limits cell growth Loss of dMyc affects protein synthesis ribosome

Knock-in Mice Myc tm1Lbox Allele knock-in IgH 3’ enhancer upstream of Myc locus Created heterozygote and homozygote

WT vs. IgH-3’E-myc mouse Lymph node Spleen WT spleen IgH-3’E-myc spleen Lymphoma in lungLymphoma in kidneyIgH-3’E-myc spleen

Mouse Model for Burkitt Lymphoma et/WIFetch?page=alleleDetail&key=39047 B cell earch/b-cellbiology/index.m HomoHet

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! ???

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: Burkitt, D. (1962). A Lymphoma Syndrome in African Children. Annals of the Royal College of Surgeons of England. 30(4): Retrieved from: 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): Retrieved from: J&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C &_version=1&_urlVersion=0&_userid=10 &md5=5ed8f5bd595b7103fdbe1b0aa055b850 J&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C &_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): Pierce, SB., Yost, C., and Andersen, S. (2008). Drosophila growth and development in absence of dMyc and dMnt. Developmental Biology. 315(2): Retrieved from: 1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C &_version=1&_urlVersion=0&_userid=10 &md5=9b9a25effa5156ae728c4d67c7b2e &_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C &_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: 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: ulltext=Sp1&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT

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