MYC’s role in Osteosarcoma & Lymphoma Lauren Spoeneman

Myc is a target of the RAS/Raf Pathway RTK GRB2  SOS  Ras  RAF  MEK  ERK  Myc MYC is transcribed in response to mitogenic signals, and it reaches peak mRNA levels within 2 hrs. mRNA half life= 10 min. Myc protein half-life = 25 min MYC regulated by growth inhibitory signals such as GSK3. http://www.nature.com/leu/journal/v17/n7/fig_tab/2402945f14.html

Myc is a transcription factor in the helix-loop-helix family Stella Pelengaris, Mike Khan & Gerard Evan. Nature Reviews Cancer 2, 764-776 (October 2002) When myc is active- MYC & MAX form a heterodimer & bind to an E-box sequence (CACGTG) near the promoter of a c-MYC target gene. Different coactivators can bind to Myc and assist with Nucleosomal acetylation which alters chromatin structure, allowing accessibility of MYC&MAX transcriptional-activator complexes to target DNA, resulting in expression of the target gene. 

Myc Protein has domains that bind both DNA and protein partners like Max Stella Pelengaris, Mike Khan & Gerard Evan. Nature Reviews Cancer 2, 764-776 (October 2002) The carboxy-terminal domain (CTD) of human c-MYC protein harbours the basic (b) helix?loop?helix (HLH) leucine zipper (LZ) motif for dimerization with its partner, MAX, and subsequent DNA binding of MYC?MAX heterodimers. The amino-terminal domain (NTD) harbors conserved 'MYC Boxes' I and II (MBI and MBII), which are essential for the transactivation of c-MYC target genes.  Yap, J. L., J. Chaauhan, and J. Kwan-Young. "Small-Molecule Inhibitors of Dimeric Transcription Factors: Antagonism of protein–protein and protein–DNA Interactions." MedChemComm 3 (2012): 541. Print.

C-Myc knockout mice is embryonic lethal with defects in vasculogenesis, angiogenesis, and primitive erythropoiesis in the yolk sac c-Myc deficiency was associated with marked defects in vasculogenesis, angiogenesis, and primitive erythropoiesis in the yolk sac. These knockout embryos when compared to wildtype tissues at day 10, exhibited small size, developmental delay, enlarged heart and pericardium, decreased yolk sac circulation, and aberrant neural tube closure. Day 10.5

Myc mutations are found in Lymphoma & Osteosarcoma Lymphoma symptoms: can occur anywhere in lymph nodes, which normally regulate the body’s immune response to antigens. Cancer symptoms include swollen lymph nodes in Groin, neck, armpit. Chest pain, coughing, trouble breathing, abdominal pain/swelling, fatigue, fever, night sweats, weight loss. Diagnosed via biopsy Osteosarcoma occurs in the long bone’s mesenchymal cells, especially in the femur, humerus and their associated joints. Most commonly metastasizes to lungs. Occurs most commonly in patients in their 2nd decade of life.. Symptom= pain. mesenchymal cells (precursors for hematopoietic, what circulates in the blood, and connective tissues like bone and cartilage). Diagnosed via X-Ray, MRI, blood test, CT scan https://www.med-ed.virginia.edu/courses/path/innes/wcd/lymphoma.cfm http://www.nlm.nih.gov/medlineplus/bonecancer.html

In lymphomas Myc mutates into an oncogene via a chromosomal translocation (814) Located on chromosome 8q24. how this is mutated at the genetic level: Simple karyotype with a t(8;14) MYC rearrangement (arrows) [46,XY,t(8;14)(q24;q32)]. This is what happens in lymphomas. Translocates from Myc to immunoglobulin gene, most commonly (85%) the Ig heavy chain at 14q32. Light chain is involved in 15% of cases at 2p12 & 22q11. Breakpoint is immediately 5’ to MYC in exon 1 (not important for the protein, noncoding). IGH breakpoint occurs 5’ to the IGH joining region Cancerous Mutation causes Myc to be constitutively expressed  unregulated expression of many other genes This translocation results in increased transcription of Myc protein because of it’s new proximity to Ig enhancers. It also experiences hypermutational mechanisms associated with Ig chains Slack, G. W., and R. D. Gascoyne. "MYC and Aggressive B-Cell Lymphomas." Advances in Anatomic Pathology 18.3 (2011): 219-28. Web.

The Myc gene is overexpressed in Osteosarcomas due to loss of INK4 Overexpression of Myc due to gene amplification associated with loss of INK4, which is a cyclin dependent kinase inhibitor. NORMALLY: Myc is involved in Cell cycle progression (drives G1  S phase, activates genes like cyclin D, and inhibit antiproliferative proteins like CKIs), Cell growth: increase cell metabolism, mitochondrial biogenesis, biosynthesis of nucelic acids, ribosomes, protein) So when Myc becomes deregulated in both lymphomas & osteosarcomas, and mutant Myc Inhibits cell differentiation and drives cell growth, vasculogenesis, reduces cell adhesion, promotes metastasis and genomic instability, and drives unrestricted cell proliferation Shimizu, T., et al. "C-MYC Overexpression with Loss of Ink4a/Arf Transforms Bone Marrow Stromal Cells into Osteosarcoma Accompanied by Loss of Adipogenesis."Oncogene 29.42 (2010): 5687-99. ProQuest Central. Web.

Current Treatments for B-cell NHL lymphoma include monoclonal antibody Rituxan Lymphoma= chemotherapy, radiation, bone marrow transplants, IL-2 which activates the body’s immune response against the cancer cells, and drugs like Rituxan/rituximab: a monoclonal antibody that binds to the surface of cancerous B-cells (which have it’s antigen on the membrane surface- CD20), which marks them for destruction by other immune cells or causes the B cell to undergo apoptosis, http://www.rituxan.com/hem/hcp/mechanism-action

Future Treatment Targets for Oncogenic Myc include Heat Shock Protein Inhibition Heat shock proteins are produced when a cell experiences stress, and they act to ensure other proteins like Myc are folding correctly post-translation. (Bottom) HSP inhibitors would prevent binding of overexpressed Myc to HSPH1, remaining in the cytosol, where CPs are ubiquitinated (Ub) and subsequently degraded by the proteasome. Briones, Javier. Blood (2015);125:1685-1686

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