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4 recordsLinked to original sources
PubMed2026

T-Cell Leukemia Cell Line Harboring Previously Undescribed CBFB::MYL11 Fusion Exhibits a Genome Profile Implicating Cytoskeletal Abnormality.

INTRODUCTION: Gene fusions involving core binding factors (CBFs), such as CBFB::MYH11, are major contributing factors to leukemia development. The pathogenic mechanism is believed to lie in abnormalities in CBF, however, myosin, the fusion partner, has received little attention. In a preliminary analysis, we identified a previously undescribed fusion transcript, CBFB::MYL11, in RNA-sequencing data from the T-cell leukemia cell line HPB-ALL. We hypothesized that leukemia cells harboring CBFB::MYH11 or CBFB::MYL11 may share a common pathological mechanism involving myosin fusion. METHODS: Fluorescence in situ hybridization was performed to analyze the structure of CBFB::MYL11 and Western blotting was performed to verify the fusion protein in HPB-ALL. Differentially expressed gene (DEG) and gene ontology (GO) analyses were performed on ME-1 harboring CBFB::MYH11 and HPB-ALL to investigate characteristics of gene expression and molecular function. RESULTS: In situ amplification of MYL11 and co-amplification of CBFB and MYL11 on a marker chromosome were observed. Elevated MYH11 and MYL11 expression and significant upregulation of genes related to the cytoskeleton were observed in the ME-1 and HPB-ALL cell lines. Bands consistent with the CBFB::MYL11 fusion protein were observed using Western blotting. CONCLUSION: This study underscores the pathological significance of cytoskeletal abnormalities in leukemia with CBFB/myosin fusion and provides a foundation for further investigation into their molecular mechanisms.

Journal Article↗
PubMed2025

Genetic Analysis of Early Neoplasia in the Breast: Next-Generation Sequencing of Flat Epithelial Atypia and Associated Ductal and Lobular Lesions.

The molecular features of invasive breast cancers (IBC) have been well-characterized, but less is known about the earlier stages of neoplasia, including oncogenic drivers in early intraductal lesions. Flat epithelial atypia (FEA) is considered the earliest recognized precursor in the low-grade neoplasia pathway, but its mutational repertoire has not been studied, and drivers of the transition to morphologically more advanced lesions are unknown. Herein, we utilized next-generation sequencing to analyze 39 synchronous lesions from 13 patients, including FEA (n = 12) or predominantly FEA with early atypical ductal hyperplasia (FEA/early atypical ductal hyperplasia [ADH], n = 5) and associated ADH (n = 2), ductal carcinoma in situ (ductal carcinoma in situ [DCIS], n = 11), lobular carcinoma in situ (n = 3), and/or IBC with ductal and/or lobular differentiation (n = 6). Aside from 1 DCIS sample, all sequenced lesions in each patient were clonally related to one another. Recurrent alterations in FEA and FEA/early ADH included PIK3CA (69%), NCOR1 (31%), CBFB (31%), RUNX1 (15%), and GATA3 (23%). The mutational repertoire of FEA was similar to The Cancer Genome Atlas luminal IBC, except CBFB and NCOR1 mutations, which were more frequent in FEA and (along with PIK3CA, FOXA1, and CDKN1B) not always identified in paired morphologically advanced lesions. Compared with FEA, DCIS had more mutations and chromosomal copy number changes, including aberrations in PI-3 kinase pathway, transcription factors, chromatin remodeling genes, and TP53. CDH1 mutations identified in lobular carcinoma in situ were absent in paired FEA. Analysis of cases with ductal and lobular heterogeneity, including Rosen's triad, confirmed the shared clonality of the ductal and lobular components with features of genetic divergence. IBC of no special type were genetically similar to DCIS, and tubular carcinomas were similar to FEA. The results reveal the mutational repertoire of FEA and the genetics of early breast neoplasia, highlighting the clonal relationships of FEA to ductal and lobular carcinomas. Luminal breast cancer-associated genetic alterations are present at the earliest morphologically recognized stages of neoplasia.

Humans↗
PubMed2026

A chromatin-informed transcriptional regulatory framework to stratify patients and guide therapy selection in triple-negative breast cancer.

Triple-negative breast cancer is an aggressive and heterogeneous breast cancer subtype with few effective targeted therapies and frequent resistance to chemotherapy. Here, we integrate transcriptional regulatory network inference with chromatin accessibility across a large-scale multi-system collection of primary tumors, patient-derived xenografts and model cell lines to quantify transcription factor activity and identify regulators that underpin triple-negative breast cancer identity. This approach prioritizes 94 high-confidence triple-negative breast cancer transcription factors whose activity capture inter-tumor heterogeneity and independently stratify patient outcome across clinical endpoints. Linking transcription factor activity to pharmacogenomic drug sensitivity profiles identifies reproducible drug-transcription factor associations across independent datasets, including NFE2L3 and CBFB activity as predictors of sensitivity to mTOR inhibition, which we validate in everolimus-treated triple-negative breast cancer patient-derived xenograft models. Collectively, we provide a transcriptional and chromatin-informed framework to capture triple-negative breast cancer regulatory state and expand transcription factor guided precision medicine to this breast cancer subtype.

Humans↗
PubMed2025

CDK12 inhibition reveals melanoma dependence on the RUNX1/CBFβ complex for genomic stability.

Cutaneous melanoma is the deadliest form of skin cancer, frequently driven by hyperactivation of the RAS/mitogen-activated protein kinase (MAPK) pathway. Cyclin-dependent kinase 12 (CDK12), a downstream effector of MAPK signaling, has emerged as a therapeutic target due to its essential role in transcriptional regulation and DNA damage repair. To identify vulnerabilities associated with CDK12 inhibition, we performed a genome-wide CRISPR-Cas9 screen and identified the Runt-related transcription factor RUNX1 and its cofactor CBFβ as synthetic lethal partners of CDK12. RUNX1 inhibition enhanced melanoma sensitivity to CDK12 inhibitors in a p53-independent manner, resulting in DNA damage accumulation and impaired repair capacity. Combined inhibition of CDK12 and RUNX1 suppressed melanoma growth in vivo. These findings identify RUNX1/CBFβ as a compensatory mechanism in CDK12-inhibited melanoma and define a synthetic lethal interaction with translational potential for combinatorial therapy.

Core Binding Factor Alpha 2 Subunit↗