Burkitt lymphoma (BL) is a B cell cancer that develops primarily in children and is associated with Epstein-Barr virus (EBV). The EBV latent membrane protein 2A (LMP2A) drives BL in part by providing constitutively active pro-survival signaling. A double transgenic mouse model of BL expressing LMP2A and the oncogene MYC (LMP2A/-MYC) develop tumors faster than mice only expressing MYC (-MYC). We previously demonstrated that p53 pathway mutations are common in -MYC tumors, but far less so in LMP2A/-MYC tumors, suggesting LMP2A signaling drives lymphomagenesis in a way that nullifies the tumor suppressive functions of p53. Here, I expand on previous work, which showed increased degradation of the cell cycle regulator p27Kip1 in LMP2A/-MYC B cells. I show for the first time that blocking two major pathways of p27Kip1 degradation prevents the accelerated tumor development driven by LMP2A. Stabilizing p27Kip1 also normalized cell cycle progression, spleen size, and splenic architecture in LMP2A/-MYC mice. Additionally, I suggest LMP2A activity is able to bypass the loss of BCL6 corepressor (BCOR) expression frequently seen in -MYC tumors and that LMP2A accelerates tumor development by upregulating expression of protein arginine methyltransferase 5 (PRMT5). My work highlights the importance of both LMP2A and MYC in BL development. By uncovering the mechanisms by which LMP2A and MYC drive lymphoma development in our model, I identify proteins that may be targeted for the future treatment of BL.

Creator

• Sora, Richard

DOI

• https://doi.org/10.21985/n2-k54z-ts20

Subject

• Biology

Language

• en

Alternate Identifier

• http://dissertations.umi.com/northwestern:14954
• etdadmin_upload_709459

Date created

• 2019-01-01

Resource type

• Dissertation

Rights statement

• In Copyright