Genomic Insights into ATRX Deletion-Driven Undifferentiated Sarcoma Development

Yiming Cai (Advisor: Francesca Cole, PhD)

     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, we demonstrate that Atrx deletion in the context of Trp53 loss markedly accelerates sarcoma initiation and progression. The resulting tumors closely recapitulate the histopathological features and transcriptional landscapes of human UPS.

   Single-cell and bulk transcriptomic profiling reveal that ATRX-deficient tumors exhibit pronounced activation of proliferative programs alongside diminished immune-related signaling pathways. Mechanistically, ATRX loss disrupts 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 identify the transcription factor RUNX1 as a central mediator of this phenotype. We further show that ATRX directly regulates Runx1 expression through H3.3 deposition at the Runx1 P2 promoter, thereby controlling isoform-specific transcription during MSC differentiation. Sustained RUNX1b expression in ATRX-deficient cells drives aberrant histone gene transcription programs, promoting continued proliferation and blocking terminal differentiation. Finally, functional genetic screening uncovers 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 vulnerability in ATRX-mutant UPS.

Advisory Committee:

• Francesca Cole, PhD, Chair
• Min Gyu Lee, PhD
• Guillermina Lozano, PhD
• Neeta Somaiah, md
• Andrea Viale, MD
• Chenghang Zong, PhD