Abstract

BAP1, a chromatin modifier, is a frequently mutated tumor suppressor in clear cell renal cell carcinoma (ccRCC). Mutations in BAP1 are associated with a more aggressive and lethal disease. However, the downstream mediators of BAP1 loss in ccRCC oncogenesis are not well understood. To better understand mechanisms of BAP1-mediated tumor suppression, I have extensively characterized the very early transcriptional mediators of BAP1 loss in a postnatal kidney-specific genetic knockout model. Because VHL loss is the initiating event in ccRCC, we modeled Bap1 loss in a Vhl-deficient background. I have found that Vhl/Bap1 double-knockout cells of PT segment S2 strongly activate the oncogenic MYC pathway. To assess the clinical relevance of the MYC pathway, I evaluated MYC target activity in the CPTAC cohort of ccRCC patients and found that it independently predicted early progression. Given the marked male predominance of ccRCC, I then examined sex differences in the early MYC pathway activation observed following Bap1 loss in the mouse model. Vhl/Bap1 double-knockout proximal tubule S2 cells from males, but not females, upregulated the MYC targets Slc3a2, Mthfd2, and Ppargc1b, suggesting that male proximal tubule cell vulnerability to MYC activation may play a role in their transformation. In addition to canonical MYC targets, I observed male-specific activation of the integrated stress response. High integrated stress response activity was independently associated with shorter progression-free survival in a multivariate Cox proportional hazards model adjusted for sex, age, Fuhrman nuclear grade, AJCC stage and BAP1 mutation status. Together, these findings identify MYC activation as a central early consequence of Bap1 loss in Vhl-deficient proximal tubule cells and reveal sex-specific differences in downstream stress responses. The clinical association of elevated MYC target activity and integrated stress response with early progression underscores their relevance to aggressive ccRCC.

Committee Chair

Li Ding

Committee Members

John Edwards; Josh Rubin; Melissa Reimers; Sanjay Jain

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Developmental, Regenerative, & Stem Cell Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

6-11-2026

Language

English (en)

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