1. Myc Lymphoma and Osteosarcoma By Patti Williams

2. What is Myc?  Located on Chromosome 8q24 (3 exons)  A proto-oncogene  Stimulates the transcription of genes causing the cell to progress through the cell cycle (G1 to S).  Involved with cell proliferation and blocks terminal cell differentiation.  Triggers apoptosis Nilsson & Cleveland; http://www.cellsignal.com/reference/pat hway/G1S.asp

3. Myc Regulation  Growth Factors stimulate cells and release myc as an immediate early gene response.  High Myc levels persist through the cell cycle and then returns to normal levels. Normal cells over expressing Myc are killed through a P53-dependent cell death pathway. Normal cells over expressing Myc are killed through a P53-dependent cell death pathway. Nilsson and Cleveland

4. Targets/Function  Myc dimerizes to Max.  Does not work unless dimerized with Max  Mnt:Max represses transcription. Myc can displace Mnt which turns on the “Myc response” thus causing transcription  Myc indirectly causes a decrease in p27 (CDK inhibitor) which adds to its involvement in promoting the cell cycle. Gardner, et al

5. Mouse Knockouts  Myc -/- = early embryonic death due to a lack of hematopoiesis  Those with decreased levels of Myc have decreased or a complete lack of proliferation and viability  Flies w/ mutated Myc are much smaller than wild type flies. The fly’s cells are small in size as well. Proof Myc influences cell and organismal size.) Proof Myc influences cell and organismal size.) Nilsson and Cleveland

6. How Myc Leads to Cancer Formation  Myc is an early response gene for practically every signal transduction pathway involved in cancer.  Myc is overexpressed in over 70% of all cancers.  Myc leads to cancer formations via translocations, amplifications, enhanced translations or through protein stability.  During Myc-based tumor formation the cell is able to avoid the checkpoints for the apoptosis pathways. The mechanisms by which they do this is not clearly understood. Nilsson and Cleveland

7. Burkitt’s Lymphoma  Burkitt’s Lymphoma is caused by a Chromosome Translocation between chromosomes 8 and 14.  The translocation occurs with immunoglobulin genes that are highly active in B cells. Having infections or other factors affecting the immune system increases the risk for developing this type of lymphoma. Having infections or other factors affecting the immune system increases the risk for developing this type of lymphoma.  Myc is translocated close to a gene that is part of the antibody heavy chain. This causes overproduction of the Myc transcription factor in the lymphocytes. Lodish, et al; thailabonline; onamercyship.org

8. Osteosarcoma  Malignant bone cancer affecting connective (soft tissue) Most often in the metaphysis regions of tubular long bones Most often in the metaphysis regions of tubular long bones Approximately 50% of cases are in the knee. Approximately 50% of cases are in the knee.  6 th most common cancer among children  Myc is over expressed due to gene amplification. (c-fos overexpression is usually present as well) Ladanyi, et al; medanswer.com; kidshealth.org; Surgical tutor.org

9. Possible Treatments  Recent studies indicate that stopping some cancers may 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 most likely exist in other cancers involving epithelial tissues.Studied only liver cancer and bone cancer in mice, but similar trends 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.

10. Resources  Adams, Amy. Stanford Report, October 13, 2004.  Gardner, L.; Lee, L.; and Dang, C. “The c-Myc Oncogenic Transcription Factor”. Encyclopedia of Cancer Second Edition, July 2002.  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”. Diagnostic Molecular Pathology 1993, Sep; 2 (3): 163-7.  Lodish, H.; Berk, A.; Matsudaira, P.; Kaiser, C.A.; Krieger, M.; Scott, M.P.; Zipursky, S.L.; and Darnell, J. Molecular Cell Biology Fifth Edition. W.H. Freeman and Company: New York, 2004. pg. 955-956.  Nilsson, J.A. and Cleveland, J.L. “Myc Pathways Provoking Cell Suicide and Cancer”. Oncogene (2003) 22: 9007-9021.   http://www.cellsignal.com/reference/pathway/G1S.asp (4/3/06) http://www.cellsignal.com/reference/pathway/G1S.asp  http://www.medanswer.com/cancer/bone-cancer.php (4/3/06) http://www.medanswer.com/cancer/bone-cancer.php  http://kidshealth.org/parent/medical/cancer/cancer_osteosarcoma.html (4/3/06) http://kidshealth.org/parent/medical/cancer/cancer_osteosarcoma.html  http://www.surgical-tutor.org.uk/default- home.htm?system/locomotor/bone_tumours.htm~right (4/3/06) http://www.surgical-tutor.org.uk/default- home.htm?system/locomotor/bone_tumours.htm~right http://www.surgical-tutor.org.uk/default- home.htm?system/locomotor/bone_tumours.htm~right  http://thailabonline.com/lymphoma1burkitt.htm (4/3/06) thailabonline.com/lymphoma1burkitt.htm  http://onamercyship.com/blog.html (4/3/06) onamercyship.com/blog.html