Abstract 1435: ATRX loss blocks the differentiation of mesenchymal stem cells and advances undifferentiated sarcoma development

Abstract Soft tissue sarcomas (STSs) are a collection of rare tumor types originated from the mesenchymal tissues. Among the over 70 histological subtypes of STS, undifferentiated sarcoma (US), which lacks any discernible morphological features of differentiated tissues, accounts for over 20% of all STSs and is correlated with high tumor grade and poor prognosis. Recent genomic profiling in US has identified p53 and ATRX among the most frequently mutated or deleted genes. ATRX is a SWI/SNF2 type of chromatin remodeling factor which functions in a histone variant H3.3-specific chaperone complex to orchestrates replication-independent nucleosome assembly at repetitive heterochromatic DNA regions including telomeres. Loss-of-function mutations occur frequently in many tumor types and is associated with the development of alternative lengthening of telomere (ALT). However, how loss of ATRX function may contribute to tumorigenesis is largely unknown. Here, we demonstrated that ATRX is required for the terminal differentiation of mouse mesenchymal stem cells (MSCs) into multiple lineages, such as adipocytes and osteocytes. Targeted deletion of Atrx in mouse MSCs, but not terminally differentiated mesenchymal lineage cells, accelerated sarcoma initiation induced by loss of p53 and significantly shortened the overall survival. Atrx-deficient tumors express high level of MSC markers such as CD44 and CD29 and exhibit pathological features highly reminiscent of human high-grade US. By analyzing the transcriptome alterations in Atrx null MSC and tumor cells, we identified a cluster of histones, highly involved in stemness maintenance, chromatin structure modifications and cell cycle, are upregulate under Atrx deletion. On the other hand, further assessment in chromatin remodeling reveals abnormal increased chromatin accessibility under Hist1/2 cluster, where most differential expressed histones are located. Transcriptomic analysis under single cell level also indicates that Atrx deficiency is associated with enhanced cell proliferation. Together, our data indicates that ATRX deficiency contributes to undifferentiated sarcoma development by inhibiting mesenchymal stem cell differentiation. Citation Format: Yiming Cai, Jun Yao, Dean Pan, Yanqing Jin, James You, Wantong Yao, Haoqiang Ying. ATRX loss blocks the differentiation of mesenchymal stem cells and advances undifferentiated sarcoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1435.