Browsing by Author "Traube, Franziska R."

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Open Access
Analysis of 3760 hematologic malignancies reveals rare transcriptomic aberrations of driver genes
(2024) Cao, Xueqi; Huber, Sandra; Ahari, Ata Jadid; Traube, Franziska R.; Seifert, Marc; Oakes, Christopher C.; Secheyko, Polina; Vilov, Sergey; Scheller, Ines F.; Wagner, Nils; Yépez, Vicente A.; Blombery, Piers; Haferlach, Torsten; Heinig, Matthias; Wachutka, Leonhard; Hutter, Stephan; Gagneur, Julien
Background. Rare oncogenic driver events, particularly affecting the expression or splicing of driver genes, are suspected to substantially contribute to the large heterogeneity of hematologic malignancies. However, their identification remains challenging. Methods. To address this issue, we generated the largest dataset to date of matched whole genome sequencing and total RNA sequencing of hematologic malignancies from 3760 patients spanning 24 disease entities. Taking advantage of our dataset size, we focused on discovering rare regulatory aberrations. Therefore, we called expression and splicing outliers using an extension of the workflow DROP (Detection of RNA Outliers Pipeline) and AbSplice, a variant effect predictor that identifies genetic variants causing aberrant splicing. We next trained a machine learning model integrating these results to prioritize new candidate disease-specific driver genes. Results. We found a median of seven expression outlier genes, two splicing outlier genes, and two rare splice-affecting variants per sample. Each category showed significant enrichment for already well-characterized driver genes, with odds ratios exceeding three among genes called in more than five samples. On held-out data, our integrative modeling significantly outperformed modeling based solely on genomic data and revealed promising novel candidate driver genes. Remarkably, we found a truncated form of the low density lipoprotein receptor LRP1B transcript to be aberrantly overexpressed in about half of hairy cell leukemia variant (HCL-V) samples and, to a lesser extent, in closely related B-cell neoplasms. This observation, which was confirmed in an independent cohort, suggests LRP1B as a novel marker for a HCL-V subclass and a yet unreported functional role of LRP1B within these rare entities. Conclusions. Altogether, our census of expression and splicing outliers for 24 hematologic malignancy entities and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers.
Open Access
Neocarzilin inhibits cancer cell proliferation via BST‑2 degradation, resulting in lipid raft-trapped EGFR
(2024) Braun, Josef; Hu, Yudong; Jauch, Adrian T.; Gronauer, Thomas F.; Mergner, Julia; Bach, Nina C.; Traube, Franziska R.; Zahler, Stefan; Sieber, Stephan A.
Neocarzilin (NCA) is a natural product exhibiting potent antimigratory as well as antiproliferative effects. While vesicle amine transport protein 1 (VAT-1) was previously shown to inhibit migration upon NCA binding, the molecular mechanisms responsible for impaired proliferation remained elusive. We here introduce a chemical probe closely resembling the structural and stereochemical features of NCA and unravel bone marrow stromal antigen 2 (BST-2) as one of the targets responsible for the antiproliferative effect of NCA in cancer cells. The antiproliferative mechanism of NCA was confirmed in corresponding BST-2 knockout (KO) HeLa cells, which were less sensitive to compound treatment. Vice versa, reconstitution of BST-2 in the KO cells again reduced proliferation upon NCA addition, comparable to that of wild-type (wt) HeLa cells. Whole proteome mass spectrometric (MS) analysis of NCA-treated wt and KO cancer cells revealed regulated pathways and showed reduced levels of BST-2 upon NCA treatment. In-depth analysis of BST-2 levels in response to proteasome and lysosome inhibitors unraveled a lysosomal degradation path upon NCA treatment. As BST-2 mediates the release of epidermal growth factor receptor (EGFR) from lipid rafts to turn on proliferation signaling pathways, reduced BST-2 levels led to attenuated phosphorylation of STAT3. Furthermore, fluorescence microscopy confirmed increased colocalization of EGFR and lipid rafts in the presence of NCA. Overall, NCA represents a versatile anticancer natural product with a unique dual mode of action and unconventional inhibition of proliferation via BST-2 degradation.