Abstract A044: Dissecting the developmental trajectory of DICER1 syndrome-associated sarcoma with genetically engineered mouse models

Abstract IA003: DICER1-related tumor predisposition: genotypes, phenotypes and mechanisms

DICER1 is an endoribonuclease that plays a critical role in microRNA (miRNA) biogenesis. DICER1 contains two catalytic ribonuclease domains: RNase IIIa and RNase IIIb, which cleave the bound precursor miRNA to generate 3p and 5p strands, respectively, of the miRNA. One strand is loaded into the RNA-induced silencing complex to mediate gene silencing. Germline loss-of-function (LOF) mutations in DICER1 are associated with DICER1-related tumor predisposition (DRTP), a rare hereditary tumour predisposition syndrome affecting mainly children and young adults. DRTP is associated with a broad spectrum of benign and malignant tumors, including pleuropulmonary blastoma (PPB), Sertoli-Leydig cell tumors, and aggressive sarcomas at multiple sites, the most common being gynecological and intra-cranial. Unlike the classical Knudson two-hit model involving biallelic inactivation, DRTP tumors typically carry a germline LOF mutation with a hotspot somatic missense mutation in the RNase IIIb catalytic domain. These somatic mutations affecting residues (e.g. D1709, E1813) selectively disrupt cleavage of 5p miRNAs, while preserving most 3p miRNA production. This creates an miRNA imbalance marked by depletion of 5p miRNAs, including tumor suppressors such as the let-7 family, which contributes to oncogenesis. We examined the effects of two of these variants using Dicer1-floxed mouse mesenchymal stem cells: the canonical RNase IIIb mutant E1813K and the non-canonical RNase IIIa mutant S1344L, which also impairs RNase IIIb activity. We show that while both variants impair 5p miRNA production and enhance 3p miRNA levels, S1344L affects only a subset of 5p miRNAs. Consistent with their differential effects on 5p miRNA production, E1813K and S1344L induce partially overlapping gene expression changes relative to wild-type DICER1 cells. When compared with a DICER1 mutant–initiated pituitary blastoma, we identify a discrete set of stabilized mRNAs, many of which promote cell proliferation. Conversely, several mRNAs encoding pro-apoptotic factors exhibit reduced stability in DICER1 mutant cells. One of the most aggressive DRTP cancers is primary intracranial sarcoma (PIS), which lacks effective therapies. Using a longitudinal primary and recurrent DRTP PIS patient tumour pair, we characterize elevated expression of myogenic transcription factor MYOD1 and concomitant downregulation of neural gene signatures in recurrent PIS. We also establish patient-derived xenograft (PDX) and primary cell models of DRTP PIS, that recapitulate human tumor biology. We demonstrate that inhibitors of MEK and CDK4/6 strongly suppressed tumour growth of DRTP PIS PDXs and induced upregulation of genes associated with neuronal differentiation. Our results suggest that disrupted neural differentiation program is associated with DRTP PIS progression and inhibition of MEK and CDK4/6 can be used to induce neural differentiation and suppress growth of DRTP PIS. Taken together, these studies have begun to identify the key pathways and vulnerabilities that characterise tumors that arise in DRTP. William D. Foulkes, Anne-Laure Chong, Hannah D. Hosein, Anais Gagne, Sidong Huang, Marc R. Fabian. DICER1-related tumor predisposition: genotypes, phenotypes and mechanisms [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr IA003.

Abstract A049: Bap1-driven soft tissue sarcomas: Mouse modeling and therapeutic strategies

Soft tissue sarcomas (STS) are rare in both pediatric and adult cancer patients, yet they remain highly lethal and understudied. Many STS subtypes, including undifferentiated pleomorphic sarcoma (UPS), exhibit significant genetic heterogeneity and lack recurrent oncogenic driver mutations, complicating the development of broadly effective therapies. A promising strategy is to design targeted treatments for subsets of STS driven by specific tumor suppressor alterations. However, the molecular pathogenesis of UPS remains poorly understood, limiting therapeutic progress. Germline and somatic mutations in BRCA1-associated protein 1 (BAP1), an epigenetic regulator, have been linked to multiple STS subtypes, yet its role in suppressing sarcoma development is unclear. Using a murine model, we recently identified BAP1 deletion as a driver event in UPS development. This model provides a platform to dissect BAP1’s functional role and to explore novel therapeutic strategies. We established well-characterized Bap1-deficient sarcoma cell lines derived from mouse models of STS driven by somatic deletion of Bap1 and Trp53. A high-throughput epigenetic inhibitor screen using the CellCyte proliferation assay was performed to identify the most effective inhibitors. Additional approaches included syngeneic and primary sarcoma mouse models, CRISPR/Cas genetic tools, flow cytometry, multiplex immunohistochemistry (IHC), single-cell RNA sequencing, and bulk RNA sequencing to evaluate the impact of epigenetic inhibitors on Bap1-driven STS and its immune-suppressive microenvironment. Bap1-deficient sarcoma cells exhibited marked sensitivity to several potent epigenetic inhibitors, including histone deacetylase inhibitors (HDACi), bromodomain and extra-terminal domain inhibitors (BETi), and histone demethylase inhibitors. Studies assessing their effects on the sarcoma immune microenvironment and human UPS cells and models are ongoing. Our findings establish Bap1 deficiency as a driver of STS development and reveal that Bap1-deficient sarcomas are highly susceptible to epigenetic inhibition. These results lay the foundation for translating epigenetic therapies into effective treatment strategies for patients with Bap1-driven STS, a population currently lacking targeted options. Xingliang Liu, William Haugh, Bryan Bell, Jianguo Huang. Bap1-driven soft tissue sarcomas: Mouse modeling and therapeutic strategies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A049.

SLF2 and SMC5 dysfunction drives HSC aging and predisposes to MDS, defining a new inherited bone marrow failure syndrome.

Locus-specific transposable element expression drives human hematopoietic stem cell disease pathophysiology

This study provides direct evidence that VEXAS-specific TE govern HSC clonal dominance, thereby uncovering a regulatory axis underlying HSC biology and disease mechanisms, opening a therapeutic strategy directed towards the repetitive genome.

HMGA2 is a highly sensitive marker for DICER1-related tumours.

AIMS DICER1 is a microRNA biogenesis enzyme that, when mutated, results in a rewiring of the transcriptome. Germline pathogenic variants (PVs) in DICER1 result in DICER1-related tumour predisposition (DRTP) characterized by 30 or more different, generally rare, paediatric or adolescent-onset tumours. One of these, pituitary blastoma, upregulates let-7 targets such as HMGA2, with overexpression at the protein level. In this study, we determined if HMGA2 upregulation involves other tumours characteristic of DRTP. METHODS AND RESULTS Seventy-eight lesions with confirmed DICER1 PVs were studied including CNS spindle cell sarcoma, Sertoli-Leydig cell tumour of the ovary, pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma of ovary or cervix, thyroid follicular nodular disease and seven other more rare diagnoses. Using immunohistochemistry and scoring any degree of nuclear staining for HMGA2 as positive, we found that all lesion types were positive. This was seen in all samples within each category (except one case), but in only 50% of thyroid lesions. Normal control tissues were uniformly negative. CONCLUSIONS The widespread expression in DICER1-related lesions, benign or malignant, suggests that HMGA2 expression is an early event in the pathogenesis. As HMGA2 is implicated in epithelial to mesenchymal transition, over-expression of HMGA2 in DICER1-related lesions could be driving this transition. Excluding thyroid lesions, immunostaining for HMGA2 shows 98% positivity in DICER1-related lesions, in DRTP or in tumours with somatic mutations. HMGA2 immunostaining could serve as a useful exclusion test; patients with lesions suspected of being DICER1-related, but negative for HMGA2, would be unlikely to benefit from germline DICER1 testing.

Cortical organoids from congenital DM1 PSCs reveal MBNL-dependent corticogenesis defects and enable preclinical testing of therapeutic compounds

Cortical organoids are established as a robust human model of CDM-associated neurodevelopmental defects, uncover MBNL-dependent mechanisms underlying early corticogenesis impairment and demonstrate the utility of this platform for translational therapeutic discovery in DM1.