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Papers by Vanesa-Sindi Ivanova

Research paper thumbnail of The Genetic Landscape of Primary Breast Marginal Zone Lymphoma Identifies a Mutational-driven Disease With Similarities to Ocular Adnexal Lymphoma

˜The œAmerican journal of surgical pathology, Jun 12, 2024

Research paper thumbnail of Molecular characterization and genetic subclassification comparison of diffuse large B-cell lymphoma (DLBCL) – real-life experience with 74 cases

Pathobiology, Dec 20, 2023

Research paper thumbnail of Two cases suggest Tropheryma whipplei as a causative agent of pulmonary marginal zone lymphoma

Research Square (Research Square), Apr 11, 2024

Background Marginal zone lymphomas of mucosa-associated lymphatic tissues (MZL of MALT) are a gro... more Background Marginal zone lymphomas of mucosa-associated lymphatic tissues (MZL of MALT) are a group of indolent B-cell neoplasms, which are thought to arise from chronic antigenic stimulation of B-cells either due to underlying chronic infection or autoimmune disease. Little is known about potential causative pathogens in pulmonary MZL (PMZL), although some data suggests a potential role of Achromobacter (A.) xylosoxidans. Methods An index case of chronic pulmonary colonisation with Tropheryma (T.) whipplei and subsequent development of PMZL was identi ed by T. whipplei speci c PCR and metagenomics whole genome sequencing (WGS). This case prompted a retrospectively conducted analysis of T. whipplei-speci c PCRs in lung tissue from PMZL patients (n = 22), other pulmonary lymphomas, and normal controls. Positive results were con rmed by metagenomics WGS. A systematic search for T. whipplei and A. xylosoxidans in our in-house metagenomics WGS dataset comprising autopsy lungs, lung biopsies and lung resection specimens (n = 181) was subsequently performed. Results A 69-year-old patient presented with weight loss and persistent pulmonary consolidation. Subsequent metagenomics WGS analysis detected T. whipplei in the resected lung specimen. An antibiotic regimen eventually eliminated the bacterium. However, the consolidation persisted, and the diagnosis of PMZL was made in a second lung resection specimen. A second case of T. whipplei-associated PMZL was subsequently detected in the retrospectively analysed PMZL cohort. Both cases showed comparatively few mutations and no mutations in genes encoding for NF-κB pathway components, suggesting that T. whipplei infection may substitute for mutations in these PMZL. None of the samples in our in-house dataset tested positive for T. whipplei. In contrast, A. xylosoxidans was frequently found in both autopsy lungs and lung biopsy / resection specimens that were not affected by PMZL (> 50%). Conclusions Our data suggests that T. whipplei colonisation of lungs may trigger PMZL as a potential driver. Systematic analyses with larger cohorts should be conducted to further support this hypothesis. The frequent detection of A. xylosoxidans in lung tissue suggests that it is a common component of the pulmonary microbiome and therefore less likely to trigger lymphomas.

Research paper thumbnail of Primary Bone Diffuse Large B-cell Lymphoma (PB-DLBCL) – a distinct extranodal lymphoma of germinal center origin, with an EZB-like mutational profile and good prognosis

Research Square (Research Square), May 15, 2023

Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is not recognized as a separate entity by t... more Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is not recognized as a separate entity by the current classi cation systems. Here, we de ne and highlight its distinctive clinical presentation, morphology, phenotype, gene expression pro le (GEP) and molecular genetics. We collected 27 respective cases and investigated their phenotype, performed gDNA panel sequencing covering 172 genes, and carried out uorescence in situ hybridisation to evaluate MYC, BCL2 and BCL6 translocations. We attempted to genetically subclassify cases using the Two-step classi er and performed GEP for cell-of-origin subtyping and in silico comparison to uncover up-and down-regulated genes as opposed to other DLBCL. Almost all cases (n=22) were germinal center B-cell-like (GCB) by immunohistochemistry and all by GEP. Additionally, PB-DLBCL has a mutational pro le similar to follicular lymphoma and nodal GCB-DLBCL, with the exception of TP53 and B2Mmutations. The GEP of PB-DLBCL is unique, and the frequency of BCL2rearrangements is lower compared to nodal GCB-DLBCL. The Two-step classi er categorised 8 of the cases as EZB, 3 as ST2 and 1 as MCD. This study comprehensively characterizes PB-DLBCL as a separate entity with distinct clinical and morpho-molecular features. These insights may aid in developing tailored therapeutic strategies and shed light on its pathogenesis.

Research paper thumbnail of Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13)

Research paper thumbnail of Interplay between the tyrosine kinases Chk, Csk and phosphatase PTPRJ is critical for regulating platelets in mice

Blood

The Src family kinases (SFKs) Src, Lyn and Fyn are essential for platelet activation and also inv... more The Src family kinases (SFKs) Src, Lyn and Fyn are essential for platelet activation and also involved in megakaryocyte (MK) development and platelet production. Platelet SFKs are inhibited by C-terminal Src kinase (Csk), which phosphorylates a conserved tyrosine in their C-terminal tail, and are activated by the receptor-type tyrosine phosphatase PTPRJ (CD148, DEP-1), which dephosphorylates the same residue. Deletion of Csk and PTPRJ in the MK lineage in mice results in increased SFK activity, but paradoxically hypoactive platelets due to negative feedback mechanisms, including upregulation of Csk homologous kinase (Chk) expression. Here, we investigate the role of Chk in platelets, functional redundancy with Csk and the physiological consequences of ablating Chk, Csk and PTPRJ in mice. Platelet count was normal in Chk knockout (KO) mice, reduced by 92% in Chk;Csk double KO (DKO) mice, and partially rescued in Chk;Csk;Ptprj triple KO (TKO) mice. Megakaryocyte numbers were significa...

Research paper thumbnail of Interplay between the tyrosine kinases Chk, Csk and phosphatase PTPRJ is critical for regulating platelets in mice

Blood

The Src family kinases (SFKs) Src, Lyn and Fyn are essential for platelet activation and also inv... more The Src family kinases (SFKs) Src, Lyn and Fyn are essential for platelet activation and also involved in megakaryocyte (MK) development and platelet production. Platelet SFKs are inhibited by C-terminal Src kinase (Csk), which phosphorylates a conserved tyrosine in their C-terminal tail, and are activated by the receptor-type tyrosine phosphatase PTPRJ (CD148, DEP-1), which dephosphorylates the same residue. Deletion of Csk and PTPRJ in the MK lineage in mice results in increased SFK activity, but paradoxically hypoactive platelets due to negative feedback mechanisms, including upregulation of Csk homologous kinase (Chk) expression. Here, we investigate the role of Chk in platelets, functional redundancy with Csk and the physiological consequences of ablating Chk, Csk and PTPRJ in mice. Platelet count was normal in Chk knockout (KO) mice, reduced by 92% in Chk;Csk double KO (DKO) mice, and partially rescued in Chk;Csk;Ptprj triple KO (TKO) mice. Megakaryocyte numbers were significa...

Research paper thumbnail of The Genetic Landscape of Primary Breast Marginal Zone Lymphoma Identifies a Mutational-driven Disease With Similarities to Ocular Adnexal Lymphoma

˜The œAmerican journal of surgical pathology, Jun 12, 2024

Research paper thumbnail of Molecular characterization and genetic subclassification comparison of diffuse large B-cell lymphoma (DLBCL) – real-life experience with 74 cases

Pathobiology, Dec 20, 2023

Research paper thumbnail of Two cases suggest Tropheryma whipplei as a causative agent of pulmonary marginal zone lymphoma

Research Square (Research Square), Apr 11, 2024

Background Marginal zone lymphomas of mucosa-associated lymphatic tissues (MZL of MALT) are a gro... more Background Marginal zone lymphomas of mucosa-associated lymphatic tissues (MZL of MALT) are a group of indolent B-cell neoplasms, which are thought to arise from chronic antigenic stimulation of B-cells either due to underlying chronic infection or autoimmune disease. Little is known about potential causative pathogens in pulmonary MZL (PMZL), although some data suggests a potential role of Achromobacter (A.) xylosoxidans. Methods An index case of chronic pulmonary colonisation with Tropheryma (T.) whipplei and subsequent development of PMZL was identi ed by T. whipplei speci c PCR and metagenomics whole genome sequencing (WGS). This case prompted a retrospectively conducted analysis of T. whipplei-speci c PCRs in lung tissue from PMZL patients (n = 22), other pulmonary lymphomas, and normal controls. Positive results were con rmed by metagenomics WGS. A systematic search for T. whipplei and A. xylosoxidans in our in-house metagenomics WGS dataset comprising autopsy lungs, lung biopsies and lung resection specimens (n = 181) was subsequently performed. Results A 69-year-old patient presented with weight loss and persistent pulmonary consolidation. Subsequent metagenomics WGS analysis detected T. whipplei in the resected lung specimen. An antibiotic regimen eventually eliminated the bacterium. However, the consolidation persisted, and the diagnosis of PMZL was made in a second lung resection specimen. A second case of T. whipplei-associated PMZL was subsequently detected in the retrospectively analysed PMZL cohort. Both cases showed comparatively few mutations and no mutations in genes encoding for NF-κB pathway components, suggesting that T. whipplei infection may substitute for mutations in these PMZL. None of the samples in our in-house dataset tested positive for T. whipplei. In contrast, A. xylosoxidans was frequently found in both autopsy lungs and lung biopsy / resection specimens that were not affected by PMZL (> 50%). Conclusions Our data suggests that T. whipplei colonisation of lungs may trigger PMZL as a potential driver. Systematic analyses with larger cohorts should be conducted to further support this hypothesis. The frequent detection of A. xylosoxidans in lung tissue suggests that it is a common component of the pulmonary microbiome and therefore less likely to trigger lymphomas.

Research paper thumbnail of Primary Bone Diffuse Large B-cell Lymphoma (PB-DLBCL) – a distinct extranodal lymphoma of germinal center origin, with an EZB-like mutational profile and good prognosis

Research Square (Research Square), May 15, 2023

Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is not recognized as a separate entity by t... more Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is not recognized as a separate entity by the current classi cation systems. Here, we de ne and highlight its distinctive clinical presentation, morphology, phenotype, gene expression pro le (GEP) and molecular genetics. We collected 27 respective cases and investigated their phenotype, performed gDNA panel sequencing covering 172 genes, and carried out uorescence in situ hybridisation to evaluate MYC, BCL2 and BCL6 translocations. We attempted to genetically subclassify cases using the Two-step classi er and performed GEP for cell-of-origin subtyping and in silico comparison to uncover up-and down-regulated genes as opposed to other DLBCL. Almost all cases (n=22) were germinal center B-cell-like (GCB) by immunohistochemistry and all by GEP. Additionally, PB-DLBCL has a mutational pro le similar to follicular lymphoma and nodal GCB-DLBCL, with the exception of TP53 and B2Mmutations. The GEP of PB-DLBCL is unique, and the frequency of BCL2rearrangements is lower compared to nodal GCB-DLBCL. The Two-step classi er categorised 8 of the cases as EZB, 3 as ST2 and 1 as MCD. This study comprehensively characterizes PB-DLBCL as a separate entity with distinct clinical and morpho-molecular features. These insights may aid in developing tailored therapeutic strategies and shed light on its pathogenesis.

Research paper thumbnail of Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13)

Research paper thumbnail of Interplay between the tyrosine kinases Chk, Csk and phosphatase PTPRJ is critical for regulating platelets in mice

Blood

The Src family kinases (SFKs) Src, Lyn and Fyn are essential for platelet activation and also inv... more The Src family kinases (SFKs) Src, Lyn and Fyn are essential for platelet activation and also involved in megakaryocyte (MK) development and platelet production. Platelet SFKs are inhibited by C-terminal Src kinase (Csk), which phosphorylates a conserved tyrosine in their C-terminal tail, and are activated by the receptor-type tyrosine phosphatase PTPRJ (CD148, DEP-1), which dephosphorylates the same residue. Deletion of Csk and PTPRJ in the MK lineage in mice results in increased SFK activity, but paradoxically hypoactive platelets due to negative feedback mechanisms, including upregulation of Csk homologous kinase (Chk) expression. Here, we investigate the role of Chk in platelets, functional redundancy with Csk and the physiological consequences of ablating Chk, Csk and PTPRJ in mice. Platelet count was normal in Chk knockout (KO) mice, reduced by 92% in Chk;Csk double KO (DKO) mice, and partially rescued in Chk;Csk;Ptprj triple KO (TKO) mice. Megakaryocyte numbers were significa...

Research paper thumbnail of Interplay between the tyrosine kinases Chk, Csk and phosphatase PTPRJ is critical for regulating platelets in mice

Blood

The Src family kinases (SFKs) Src, Lyn and Fyn are essential for platelet activation and also inv... more The Src family kinases (SFKs) Src, Lyn and Fyn are essential for platelet activation and also involved in megakaryocyte (MK) development and platelet production. Platelet SFKs are inhibited by C-terminal Src kinase (Csk), which phosphorylates a conserved tyrosine in their C-terminal tail, and are activated by the receptor-type tyrosine phosphatase PTPRJ (CD148, DEP-1), which dephosphorylates the same residue. Deletion of Csk and PTPRJ in the MK lineage in mice results in increased SFK activity, but paradoxically hypoactive platelets due to negative feedback mechanisms, including upregulation of Csk homologous kinase (Chk) expression. Here, we investigate the role of Chk in platelets, functional redundancy with Csk and the physiological consequences of ablating Chk, Csk and PTPRJ in mice. Platelet count was normal in Chk knockout (KO) mice, reduced by 92% in Chk;Csk double KO (DKO) mice, and partially rescued in Chk;Csk;Ptprj triple KO (TKO) mice. Megakaryocyte numbers were significa...