Browsing by Author "Dehner, Carina"

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    BCL-XL Protects ASS1-Deficient Cancers from Arginine Starvation-Induced Apoptosis
    (American Association for Cancer Research, 2025) Panda, Prashanta Kumar; Paschoalini Mafra, Ana Carolina; Bastos, Alliny C. S.; Cao, Li; Bonet, Maria Serra; Brashears, Caitlyn B.; Chen, Ethan Yang; Benedict-Hamilton, Heather M.; Ehrhardt, William; Bomalaski, John; Dehner, Carina; Rogers, Leonard C.; Oyama, Toshinao; Van Tine, Brian A.; Pathology and Laboratory Medicine, School of Medicine
    Purpose: Argininosuccinate synthetase 1 (ASS1) silencing in carcinomas and sarcomas leads to a dependence on extracellular arginine for survival. Arginine deprivation therapies, such as PEGylated arginine deiminase (ADI-PEG20), have shown limited effectiveness, which may be due to underlying mechanisms that inhibit apoptosis. Experimental design: The effects of ADI-PEG20 on cell-cycle regulation, apoptosis, and BCL-XL-mediated survival pathways in ASS1-deficient cancer cells were determined. The mechanism of cell death protection was determined by assessing caspase and PARP cleavage, CDK2 activity, MCL1 expression, and the interactions among BCL-XL, BAX, and BAK. In vitro synergy was determined, and in vivo efficacy was modeled. Results: Treatment with ADI-PEG20 led to reduced CDK2 activity and inhibited cell-cycle progression but did not induce significant cell death. BCL-XL was found to bind to BAX and BAK, preventing the initiation of apoptosis despite arginine starvation. Inhibition of BCL-XL allowed proapoptotic BAX and BAK to initiate the intrinsic apoptosis pathway, leading to increased cell death. This was found to be synergistic in vitro and efficacious in combination in vivo. Conclusions: The study identifies BCL-XL as a key factor limiting the efficacy of arginine starvation therapies. Combining BCL-XL inhibitors with arginine deprivation strategies may overcome this resistance and enhance therapeutic outcomes. These findings provide a strong preclinical rationale for testing this combination approach in phase 1 clinical trials for ASS1-deficient cancers.
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    Epithelioid Inflammatory Myofibroblastic Sarcoma: Case Series With a First Report of CLTC::ALK Fusion in an Aggressive Disease
    (Wiley, 2025) Maharjan, Daisy; Dehner, Carina; Alani, Ali; Bell, Robert; Segura, Sheila; Pathology and Laboratory Medicine, School of Medicine
    Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare and clinically aggressive variant of inflammatory myofibroblastic tumor (IMT). It typically presents in children and young adults, often affecting the abdominal cavity. It is characterized by the presence of plump, polyhedral, and epithelioid cells, and a distinctive nuclear or perinuclear ALK staining on immunohistochemistry. Various ALK fusion partners have been identified in EIMS, including RANBP2, RRBP1, EML4, and VCL. In this report, we present four cases of EIMS involving the abdominal cavity, including the first case with a CLTC::ALK fusion, which has previously been associated only with nonaggressive IMT.
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    Genomic and Transcriptomic Characterization of Protein Kinase C Fusion Melanocytic Neoplasms With Distinctive Hypopigmented Histomorphology: A Single‐Institution Study
    (Wiley, 2025) Li, Aofei; Umphress, Brandon; Dehner, Carina; Jones, Ryan; Toral, Keller; Warren, Simon; Alomari, Ahmed K.; Pathology and Laboratory Medicine, School of Medicine
    Background: Genomic fusions involving Protein Kinase C (PKC or PRKC) have been classically identified in a subset of melanocytic neoplasms with heavy melanin pigmentation as described in older series. They were recently reclassified from the pigmented epithelioid melanocytoma (PEM) category to the blue nevus (BN) category in the fifth edition of the World Health Organization (WHO) Classification of Skin Tumors. Methods: Herein, we report a series of eight mostly hypopigmented PRKC fusion melanocytic tumors with novel comprehensive molecular characterization. Clinical, histopathologic, and immunohistochemical findings were reviewed. Next-generation sequencing (NGS) data on genomic and transcriptomic levels were explored. Results: Histomorphology showed a biphasic pattern with hypercellular areas and hypocellular areas with dense fibrotic stroma and collagen trapping. The clinical courses were uncomplicated after excisions. NGS revealed three cases of PRKCB fusion and five cases of PRKCA fusions. RNA differential analysis against six blue nevi showed a group of genes with significantly higher transcription levels and strong enrichment in the direct p53 effectors gene set. PRKC fusion tumors also demonstrated significantly stronger p53 IHC staining. Conclusion: We further expand the morphologic spectrum of PRKC fusion melanocytic tumors and provide insight into their morphologic identification. Our novel transcriptome-level findings provide insight into the nuanced molecular events and new evidence for classification.