Myc Myc Lymphoma and OsteosarcomaLymphoma and Osteosarcoma

By Patti WilliamsBy Patti Williams

What is Myc?What is Myc? Located on Chromosome Located on Chromosome

8q24 (3 exons)8q24 (3 exons) A proto-oncogeneA proto-oncogene Stimulates the transcription Stimulates the transcription

of genes causing the cell to of genes causing the cell to progress through the cell progress through the cell cycle (G1 to S).cycle (G1 to S).

Involved with cell Involved with cell proliferation and blocks proliferation and blocks terminal cell differentiation.terminal cell differentiation.

Triggers apoptosisTriggers apoptosis

Nilsson & Cleveland; http://www.cellsignal.com/reference/pathway/G1S.asp

Myc RegulationMyc Regulation

Growth Factors stimulate cells and release Growth Factors stimulate cells and release myc as an immediate early gene myc as an immediate early gene response.response.

High Myc levels persist through the cell High Myc levels persist through the cell cycle and then returns to normal levels.cycle and then returns to normal levels. Normal cells over expressing Myc are killed Normal cells over expressing Myc are killed

through a P53-dependent cell death pathway.through a P53-dependent cell death pathway.

Nilsson and Cleveland

Targets/FunctionTargets/Function Myc dimerizes to Max. Myc dimerizes to Max. Does not work unless Does not work unless

dimerized with Maxdimerized with Max Mnt:Max represses Mnt:Max represses

transcription. Myc can transcription. Myc can displace Mnt which turns displace Mnt which turns on the “Myc response” on the “Myc response” thus causing transcriptionthus causing transcription

Myc indirectly causes a Myc indirectly causes a decrease in p27 (CDK decrease in p27 (CDK inhibitor) which adds to its inhibitor) which adds to its involvement in promoting involvement in promoting the cell cycle.the cell cycle.

Gardner, et al

Mouse KnockoutsMouse Knockouts

Myc -/- = early embryonic death due to a Myc -/- = early embryonic death due to a lack of hematopoiesislack of hematopoiesis

Those with decreased levels of Myc have Those with decreased levels of Myc have decreased or a complete lack of decreased or a complete lack of proliferation and viabilityproliferation and viability

Flies w/ mutated Myc are much smaller Flies w/ mutated Myc are much smaller than wild type flies. The fly’s cells are than wild type flies. The fly’s cells are small in size as well. small in size as well. Proof Myc influences cell and organismal Proof Myc influences cell and organismal

size.)size.)Nilsson and Cleveland

How Myc Leads to Cancer How Myc Leads to Cancer FormationFormation

Myc is an early response gene for practically Myc is an early response gene for practically every signal transduction pathway involved in every signal transduction pathway involved in cancer.cancer.

Myc is overexpressed in over 70% of all Myc is overexpressed in over 70% of all cancers.cancers.

Myc leads to cancer formations via Myc leads to cancer formations via translocations, amplifications, enhanced translocations, amplifications, enhanced translations or through protein stability.translations or through protein stability.

During Myc-based tumor formation the cell is During Myc-based tumor formation the cell is able to avoid the checkpoints for the apoptosis able to avoid the checkpoints for the apoptosis pathways. The mechanisms by which they do pathways. The mechanisms by which they do this is not clearly understood.this is not clearly understood.

Nilsson and Cleveland

Burkitt’s LymphomaBurkitt’s Lymphoma Burkitt’s Lymphoma is caused Burkitt’s Lymphoma is caused

by a Chromosome by a Chromosome Translocation between Translocation between chromosomes 8 and 14.chromosomes 8 and 14.

The translocation occurs with The translocation occurs with immunoglobulin genes that are immunoglobulin genes that are highly active in B cells. highly active in B cells.

Having infections or other Having infections or other factors affecting the immune factors affecting the immune system increases the risk for system increases the risk for developing this type of developing this type of lymphoma.lymphoma.

Myc is translocated close to a Myc is translocated close to a gene that is part of the gene that is part of the antibody heavy chain. This antibody heavy chain. This causes overproduction of the causes overproduction of the Myc transcription factor in the Myc transcription factor in the lymphocytes.lymphocytes.

Lodish, et al; thailabonline; onamercyship.org

OsteosarcomaOsteosarcoma

Malignant bone cancer affecting Malignant bone cancer affecting connective (soft tissue) connective (soft tissue) Most often in the metaphysis regions of Most often in the metaphysis regions of

tubular long bonestubular long bones Approximately 50% of cases are in the knee.Approximately 50% of cases are in the knee.

66thth most common cancer among children most common cancer among children Myc is over expressed due to gene Myc is over expressed due to gene

amplification. (c-fos overexpression is amplification. (c-fos overexpression is usually present as well)usually present as well)

Ladanyi, et al; medanswer.com; kidshealth.org; Surgical tutor.org

Possible TreatmentsPossible Treatments Recent studies indicate that stopping some cancers may Recent studies indicate that stopping some cancers may

be as simple as turning off the myc gene.be as simple as turning off the myc gene.• Modified Myc genes to respond to antibiotic doxycycline.Modified Myc genes to respond to antibiotic doxycycline.• Studied only liver cancer and bone cancer in mice, but similar trends Studied only liver cancer and bone cancer in mice, but similar trends

most likely exist in other cancers involving epithelial tissues.most likely exist in other cancers involving epithelial tissues.• Genes returned to normal, didn’t just die. Genes returned to normal, didn’t just die. • Need to find a drug that will bind to human Myc.Need to find a drug that will bind to human Myc.

Nilsson & Cleveland Adams, A.

ResourcesResources Adams, Amy. Stanford Report, October 13, 2004.Adams, Amy. Stanford Report, October 13, 2004. Gardner, L.; Lee, L.; and Dang, C. “The c-Myc Oncogenic Transcription Gardner, L.; Lee, L.; and Dang, C. “The c-Myc Oncogenic Transcription

Factor”. Factor”. Encyclopedia of CancerEncyclopedia of Cancer Second Edition, July 2002. Second Edition, July 2002. Ladanyi, M.; Park, C.K.; Lewis R.; Jhanwar, S.C.; Healey, J.H.; Huvos, H.J. Ladanyi, M.; Park, C.K.; Lewis R.; Jhanwar, S.C.; Healey, J.H.; Huvos, H.J.

“Sporadic Amplification of the Myc gene in Human Osteosarcomas”. “Sporadic Amplification of the Myc gene in Human Osteosarcomas”. Diagnostic Molecular PathologyDiagnostic Molecular Pathology 1993, Sep; 2 (3): 163-7. 1993, Sep; 2 (3): 163-7.

Lodish, H.; Berk, A.; Matsudaira, P.; Kaiser, C.A.; Krieger, M.; Scott, M.P.; Lodish, H.; Berk, A.; Matsudaira, P.; Kaiser, C.A.; Krieger, M.; Scott, M.P.; Zipursky, S.L.; and Darnell, J. Zipursky, S.L.; and Darnell, J. Molecular Cell BiologyMolecular Cell Biology Fifth Edition. W.H. Fifth Edition. W.H. Freeman and Company: New York, 2004. pg. 955-956.Freeman and Company: New York, 2004. pg. 955-956.

Nilsson, J.A. and Cleveland, J.L. “Myc Pathways Provoking Cell Suicide and Nilsson, J.A. and Cleveland, J.L. “Myc Pathways Provoking Cell Suicide and Cancer”. Cancer”. OncogeneOncogene (2003) 22: 9007-9021. (2003) 22: 9007-9021.

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(4/3/06)(4/3/06) http://www.surgical-tutor.org.uk/default-home.htm?system/locomotor/http://www.surgical-tutor.org.uk/default-home.htm?system/locomotor/

bone_tumours.htm~right bone_tumours.htm~right (4/3/06)(4/3/06) http://thailabonline.com/lymphoma1burkitt.htmhttp://thailabonline.com/lymphoma1burkitt.htm (4/3/06)(4/3/06) http://http://onamercyship.com/blog.html onamercyship.com/blog.html (4/3/06)(4/3/06)