Phenotypes and Gene Ontology - Burkitt Lymphoma and MYC

This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.

Phenotypes

Due to MYC being an oncogene, many human cancers can be linked to an overexpression of MYC. The phenotypes of cells bearing overexpressed MYC proteins often result in "morphological abnormalties". These abnormalties can often be associated with differences in cell size, irregular control of the cell cycle, insensitivity to growth factors, incapable of differentiation, increased rates of apoptosis, and other genetic instabilities.(3) MYC has been shown to regulate many other target genes. With disruptions in MYC, signaling to these target genes is irregular and can often lead to other phenotypes that display cancerous properties. One of these target genes is involved in the WNT pathway and leads to irregular mammary cells and thus breast cancer.(4)

The figure on the right shows the functions in which MYC normally participates. Mutations arising in MYC can lead to the cellular phenotypes as noted above. Image taken from canceruptodate.com

MYC Phenotype in Drosophila

The homolog of MYC in Drosphila melanogastor is known as diminutive (dm). The photo on the left displays the effects of a dm null mutant (far left) compared to dm null mutant/dMnt mutant (middle) and control larvae (right). With the presence of a dm null mutation it is displayed that there is severe growth defects. In the null mutants, 90% of the larvae died 5 days after egg deposition. The loss of the dMnt gene coordinated with the dm null mutant (middle larvae) showed that the presence of dMnt negatively regulated larvae growth. This can be seen in the image through the expression of dMnt with the dm null mutant compared to the dm null/dMnt mutant. The expression of endogenous dMnt with the dm null mutant (left) grew very little in comparison with the dm null and dMnt mutant. From this experiment it is shown that dm is involved with organismal growth. (7) Due to the increased size of the dm/dMnt mutant there may possibly be some underlying proteins involved that rescue the growth of the organism.

Figure 1. Figure 1 shows the salivary glands of control, dm/dMnt mutants, and dm null mutants. The small size of the salivary glands of the dm null mutant is a result of reduced endoreplication. Endoreplication is the process of DNA replication without the cell going through mitotic divisions and results in increases in ploidy number. To accomodate for the increase in DNA the cell also increases in size. The dm/dMnt mutants show an increase in size, again emphasizing the fact that dMnt negatively regulates growth. The salivary glands in drosophila are one of the best documented cells that display endoreplication and an increase in ploidy number.(7)

Burkitt Lymphoma Phenotype

For an overview of the phenotypes associated with Burkitt Lymphoma please visit the following link:
Burkitt Lymphoma Overview Particularly the pathophysiology.

The image to the left is of a child suffering from the endemic form of Burkitt Lymphoma.(5)

Mouse Model of Burkitt Lymphoma

A knock-in target mutation placed the Igh-3'-Enhancer upstream of the MYC locus. By creating this mutation it created a genetic variation that closely resembles the translocation events that occur in Burkitt Lymphoma. When the results of the experiments were shown, the knock-in mutation proved to be very close in the resemblence of symptoms experience in humans afflicted by Burkitt Lymphoma. Many models have been created before this particular knock-in mutation but none have served to closely resemble Burkitt Lymphoma. (8) Below are the systems that were affected in both homozygous (left column) and heterozygous (right column). Interestingly both of these mice strains can be used for effective models for studying Burkitt Lymphoma. (10)

The image below shows organs and histological stains that were taken from the mice with the IgH-3'-Enhancer knock-in. Panel A shows enlarged lymphnodes (top) and spleen (bottom). Panel B shows histology of a wild-type spleen. Panels C and D (at higher magnification) shows spleen histology of mouse with lymphoma. Notice the large number of cells present compared to panel B due to macrophages getting rid of the apoptotic cells. Panel E shows the lymphoma present in lungs and Panel F shows lymphoma in kidney. (8) The presence of the lymphoma in the lungs and kidneys is due to Burkitt Lymphomas capability, like all cancers, to metastisize.

"Burkitt" Mice

The images above were taken from another paper that also placed the MYC gene in coordination with the IgH-3'-Enhancer to get an idea of what the mice may have looked like. (9) The tumors appear to be affecting areas where lymph organs are located.

Gene Ontology

The MYC protein can be found in all three of the gene ontology (GO) categories which include biological processes, molecular function, and cellular component.

Biological Processes
Some of the biological processes that MYC is involved with include transcription, cell proliferation, and cell cycle arrest.

Molecular Function
The molecular functions of MYC are DNA binding, protein binding, and transcription factor activity.

Cellular Component
As MYC is involved with DNA binding, protein binding, and processes like transcription and cell cycle arreast it is of no surprise that the only cellular component in which MYC is found is in the nucleus.

For a complete breakdown of the GO annotation please visit EMBL-EBI

References:
1EMBL-EBI
2Uniprot
3Rothermund et al. (2005). C-Myc–Independent Restoration of Multiple Phenotypes by Two C-Myc Target Genes with Overlapping Functions. Cancer Research, (65). 2097-2107. Retrieved from: http://cancerres.aacrjournals.org/cgi/content/full/65/6/2097
4Cowling et al. (2007). c-Myc Transforms Human Mammary Epithelial Cells through Repression of the Wntand SFRP1 Inhibitors DKK1. Molecular and Cellular Biology, (27)14. 5135-5146. Retrieved from: http://mcb.asm.org/cgi/content/full/27/14/5135?maxtoshow=&HITS=&hits=&RESULTFORMAT=&fulltext=MYC+AND+WNT+AND+Breast+cancer&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
5canceruptodate.com
6emedicine
7Pierce, 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-4RFJ4N1-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=9b9a25effa5156ae728c4d67c7b2e772
8Boxer, 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
9Mice photos
10Affected Systems Table

Contact Info: Deeter Neumann, [email protected], May 14, 2009