Dissertations and Theses (Open Access)

Author ORCID Identifier

0000-0003-3533-1953

Date of Graduation

8-2026

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Haoqiang Ying

Committee Member

Guillermina Lozano

Committee Member

Neeta Somaiah

Committee Member

Andrea Viale

Committee Member

Min Gyu Lee

Committee Member

Chenghang Zong

Abstract

Undifferentiated pleomorphic sarcoma (UPS) is an aggressive soft-tissue malignancy with limited targeted therapeutic options. Genomic studies have revealed that UPS frequently harbors alterations in the chromatin remodeler ATRX, which often co-occur with loss of the tumor suppressor TP53. However, the mechanisms through which ATRX constrains mesenchymal tumorigenesis remain poorly understood. Here, using a mesenchymal lineage–specific genetically engineered mouse model, I demonstrated that Atrx deletion in the context of Trp53 loss markedly accelerates sarcoma initiation and progression. The resulting tumors closely recapitulated the histopathological features and transcriptional landscapes of human UPS.

Single-cell and bulk transcriptomic profiling revealed that Atrx-deficient tumors exhibit pronounced activation of proliferative programs alongside dysregulation of immune-related signaling pathways. Mechanistically, Atrx loss disrupted the differentiation capacity of mesenchymal stem/progenitor cells (MSCs) and prevents proper cell-cycle exit during lineage commitment. Integrative analyses of transcriptomic and chromatin accessibility datasets identified the transcription factor Runx1 as a central mediator of this phenotype. I further showed that Atrx directly regulates Runx1 expression through H3.3 deposition at the Runx1 P2 promoter, thereby controlling isoform-specific transcription during MSC differentiation. Sustained Runx1 P2 driven Runx1b expression in Atrx-deficient cells drives aberrant histone gene transcription programs, promoting continued proliferation and blocking terminal differentiation. Finally, functional genetic screening uncovered a selective dependency on the RUNX1/CBFB complex in Atrx-deficient UPS cells. Together, these findings uncover an Atrx loss–driven, Runx1-dependent mechanism linking impaired MSC differentiation to sarcomagenesis and highlight the RUNX1/CBFB complex as a potential therapeutic target in ATRX-mutant UPS patients.

Keywords

Soft tissue sarcoma, Undifferentiated sarcoma, Genetically engineered mouse model, ATRX, Mesenchymal stem cell, Differentiation, Epigenomics, RUNX1

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Available for download on Monday, August 07, 2028

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