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1. Cyclin dependent kinase 4/6 inhibitor palbociclib synergizes with BCL2 inhibitor venetoclax in experimental models of mantle cell lymphoma without RB1 deletion

Author

Malarikova, Diana, Jorda, Radek, Kupcova, Kristyna, Senavova, Jana, Dolnikova, Alexandra, Pokorna, Eva, Kazantsev, Dmitry, Nozickova, Kristina, Sovilj, Dana, Bellanger, Celine, Chiron, David, Andera, Ladislav, Krystof, Vladimir, Strnad, Miroslav, Helman, Karel, Klanova, Magdalena, Trneny, Marek, Havranek, Ondrej, and Klener, Pavel

Published
2024
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3. A deep intronic recurrent CHEK2 variant c.1009-118_1009-87delinsC affects pre-mRNA splicing and contributes to hereditary breast cancer predisposition

Author

Zemankova, Petra, primary, Cerna, Marta, additional, Horackova, Klara, additional, Ernst, Corinna, additional, Soukupova, Jana, additional, Borecka, Marianna, additional, Blümcke, Britta, additional, Cerna, Leona, additional, Cerna, Monika, additional, Curtisova, Vaclava, additional, Dolezalova, Tatana, additional, Duskova, Petra, additional, Dvorakova, Lenka, additional, Foretova, Lenka, additional, Havranek, Ondrej, additional, Hauke, Jan, additional, Hahnen, Eric, additional, Hodulova, Miloslava, additional, Hovhannisyan, Milena, additional, Hruskova, Lucie, additional, Janatova, Marketa, additional, Janikova, Maria, additional, Jelinkova, Sandra, additional, Just, Pavel, additional, Kosarova, Marcela, additional, Koudova, Monika, additional, Krutilkova, Vera, additional, Machackova, Eva, additional, Matejkova, Katerina, additional, Michalovska, Renata, additional, Misove, Adela, additional, Nehasil, Petr, additional, Nemcova, Barbora, additional, Novotny, Jan, additional, Panczak, Ales, additional, Pesek, Pavel, additional, Scheinost, Ondrej, additional, Springer, Drahomira, additional, Stastna, Barbora, additional, Stranecky, Viktor, additional, Subrt, Ivan, additional, Tavandzis, Spiros, additional, Tureckova, Eva, additional, Vesela, Kamila, additional, Vlckova, Zdenka, additional, Vocka, Michal, additional, Wappenschmidt, Barbara, additional, Zima, Tomas, additional, Kleibl, Zdenek, additional, and Kleiblova, Petra, additional

Published
2024
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4. A comprehensive study evaluating germline FANCG variants in predisposition to breast and ovarian cancer.

Author

Soukupova, Jana, Stastna, Barbora, Kanwal, Madiha, Hojny, Jan, Zemankova, Petra, Borecka, Marianna, Cerna, Leona, Cerna, Marta, Cerna, Monika, Curtisova, Vaclava, Dolezalova, Tatana, Duskova, Petra, Foretova, Lenka, Havranek, Ondrej, Horackova, Klara, Hovhannisyan, Milena, Hruskova, Lucie, Chvojka, Stepan, Janatova, Marketa, and Janikova, Maria

Subjects
FANCONI'S anemia, GENETIC testing, MISSENSE mutation, DNA repair, DNA damage, OVARIAN cancer
Abstract

Background: Monoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear. Methods: Here, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk. Results: The frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss‐of‐heterozygosity of the wild‐type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations. Conclusion: Our study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC. [ABSTRACT FROM AUTHOR]

Published
2024
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6. B-Cell Receptor Signaling and Beyond: The Role of Igα (CD79a)/Igβ (CD79b) in Normal and Malignant B Cells.

Author

Tkachenko, Anton, Kupcova, Kristyna, and Havranek, Ondrej

Subjects
B cells, CANCER cells, SIGNALS & signaling, POST-translational modification, B cell receptors, CYTOLOGY
Abstract

B-cell receptor (BCR) is a B cell hallmark surface complex regulating multiple cellular processes in normal as well as malignant B cells. Igα (CD79a)/Igβ (CD79b) are essential components of BCR that are indispensable for its functionality, signal initiation, and signal transduction. CD79a/CD79b-mediated BCR signaling is required for the survival of normal as well as malignant B cells via a wide signaling network. Recent studies identified the great complexity of this signaling network and revealed the emerging role of CD79a/CD79b in signal integration. In this review, we have focused on functional features of CD79a/CD79b, summarized signaling consequences of CD79a/CD79b post-translational modifications, and highlighted specifics of CD79a/CD79b interactions within BCR and related signaling cascades. We have reviewed the complex role of CD79a/CD79b in multiple aspects of normal B cell biology and how is the normal BCR signaling affected by lymphoid neoplasms associated CD79A/CD79B mutations. We have also summarized important unresolved questions and highlighted issues that remain to be explored for better understanding of CD79a/CD79b-mediated signal transduction and the eventual identification of additional therapeutically targetable BCR signaling vulnerabilities. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Tonic B-cell receptor signaling in diffuse large B-cell lymphoma

Author

Havranek, Ondrej, Xu, Jingda, Köhrer, Stefan, Wang, Zhiqiang, Becker, Lisa, Comer, Justin M., Henderson, Jared, Ma, Wencai, Man Chun Ma, John, Westin, Jason R., Ghosh, Dipanjan, Shinners, Nicholas, Sun, Luhong, Yi, Allen F., Karri, Anusha R., Burger, Jan A., Zal, Tomasz, and Davis, R.Eric

Published
2017
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8. Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib Synergizes with BH3-Mimetics in Experimental Models of Relapsed/Refractory Mantle Cell Lymphoma

Author

Malarikova, Diana, primary, Jorda, Radek, additional, Dolníková, Alexandra, additional, Havranek, Ondrej, additional, Pokorna, Eva, additional, Kazantsev, Dmitry, additional, Sovilj, Dana, additional, Helman, Karel, additional, Klanova, Magdalena, additional, Andera, Ladislav, additional, Strnad, Miroslav, additional, Chiron, David, additional, Trneny, Marek, additional, and Klener, Pavel, additional

Published
2022
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9. Antigen-Independent, Autonomous B-Cell Receptor Signaling in Diffuse Large B-Cell Lymphoma

Author

Eken, Janneke A., primary, Koning, Marvyn T., additional, Sepulveda Yanez, Julieta H., additional, van Bergen, Cornelis A.M., additional, Quinten, Edwin, additional, Kupcova, Kristyna, additional, Havranek, Ondrej, additional, De Groen, Ruben A.L., additional, Vermaat, Joost S.P., additional, de Jong, Daphne, additional, Kluin, Philip, additional, Cleven, Arjen, additional, Jumaa, Hassan, additional, and Veelken, Hendrik, additional

Published
2022
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11. Inhibition of PIM Kinases in DLBCL Targets MYC Transcriptional Program and Augments the Efficacy of Anti-CD20 Antibodies

Author

Szydłowski, Maciej, primary, Garbicz, Filip, additional, Jabłońska, Ewa, additional, Górniak, Patryk, additional, Komar, Dorota, additional, Pyrzyńska, Beata, additional, Bojarczuk, Kamil, additional, Prochorec-Sobieszek, Monika, additional, Szumera-Ciećkiewicz, Anna, additional, Rymkiewicz, Grzegorz, additional, Cybulska, Magdalena, additional, Statkiewicz, Małgorzata, additional, Gajewska, Marta, additional, Mikula, Michał, additional, Gołas, Aniela, additional, Domagała, Joanna, additional, Winiarska, Magdalena, additional, Graczyk-Jarzynka, Agnieszka, additional, Białopiotrowicz, Emilia, additional, Polak, Anna, additional, Barankiewicz, Joanna, additional, Puła, Bartosz, additional, Pawlak, Michał, additional, Nowis, Dominika, additional, Golab, Jakub, additional, Tomirotti, Andrea M., additional, Brzózka, Krzysztof, additional, Pacheco-Blanco, Mariana, additional, Kupcova, Kristyna, additional, Green, Michael R., additional, Havranek, Ondrej, additional, Chapuy, Bjoern, additional, and Juszczyński, Przemysław, additional

Published
2021
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12. Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib Synergizes with BCL2 Inhibitor Venetoclax in Experimental Models of Chemotherapy Refractory Mantle Cell Lymphoma

Author

Malarikova, Diana, primary, Jorda, Radek, additional, Dolnikova, Alexandra, additional, Pokorna, Eva, additional, Kazantsev, Dmitry, additional, Havranek, Ondrej, additional, Helman, Karel, additional, Klanova, Magdalena, additional, Strnad, Miroslav, additional, Trneny, Marek, additional, and Klener, Pavel, additional

Published
2021
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13. Is It Better to Start Treatment with ABVD and Continue with PET2-Adapted Approach or Should We Use 2 Cycles of Beacopp Escalated and 2 Cycles of ABVD and Irradiation in Early Unfavorable Hodgkin Lymphoma?

Author

Mocikova, Heidi, primary, Markova, Jana, additional, Gaherova, Lubica, additional, Maco, Maria, additional, Sykorova, Alice, additional, Belada, David, additional, Lukasova, Marie, additional, Prochazka, Vit K, additional, Hradska, Katarina, additional, Ďuraš, Juraj, additional, Havranek, Ondrej, additional, and Kozak, Tomas, additional

Published
2021
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14. Anti-apoptotic MCL1 Protein Represents Critical Survival Molecule for Most Burkitt Lymphomas and BCL2-negative Diffuse Large B-cell Lymphomas

Author

Klanova, Magdalena, primary, Kazantsev, Dmitry, additional, Pokorna, Eva, additional, Zikmund, Tomas, additional, Karolova, Jana, additional, Behounek, Matej, additional, Renesova, Nicol, additional, Sovilj, Dana, additional, Kelemen, Cristina D., additional, Helman, Karel, additional, Jaksa, Radek, additional, Havranek, Ondrej, additional, Andera, Ladislav, additional, Trneny, Marek, additional, and Klener, Pavel, additional

Published
2021
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15. Overexpression of CD200 is a stem cell-specific mechanism of immune evasion in AML

Author

Herbrich, Shelley, primary, Baran, Natalia, additional, Cai, Tianyu, additional, Weng, Connie, additional, Aitken, Marisa J L, additional, Post, Sean M, additional, Henderson, Jared, additional, Shi, Chunhua, additional, Havranek, Ondrej, additional, Richard-Carpentier, Guillame, additional, Sauvageau, Guy, additional, Baggerly, Keith, additional, Al-Atrash, Gheath, additional, Davis, R Eric, additional, Daver, Naval, additional, Zha, Dongxing, additional, and Konopleva, Marina, additional

Published
2021
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17. Overcoming NOTCH1-Driven Chemoresistance in T-Cell Acute Lymphoblastic Leukemia Via Metabolic Intervention with Oxphos Inhibitor

Author

Baran, Natalia, Lodi, Alessia, Dhungana, Yogesh, Sweeney, Shannon RENEE, Renu, Pandey, Herbrich, Shelley, Hoff, Fieke W, Skwarska, Anna, Kaplan, Mecit, Kuruvilla, Vinitha Mary, Cavazos, Antonio, Warmoes, Marc, Rojas-Sutterlin, Shanti, Haman, Andre, Veiga, Diogo Troggian, Furudate, Ken, Ma, Helen, Harutyunyan, Karine, Yang, Wentao, Gagea, Mihai, Du, Di, Daher, May, Garcia, Luciana Melo, Piya, Sujan, Ruvolo, Vivian, Shanmugavelandy, Sriram, Feng, Ningping, Gay, Jason P, Havranek, Ondrej, Henderson, Jared, Tomczak, Katarzyna, Kaminski, Marcin, Herranz, Daniel, Ferrando, Adolfo, Jabbour, Elias, Di Francesco, Maria E, Teachey, David T., Horton, Terzah M., Rezvani, Katayoun, Yang, Jun J., Kornblau, Steven M., Davis, Eric, Takahashi, Koichi, Andreeff, Michael, Marszalek, Joseph R, Lorenzi, Philip, Yu, Jiyang, Tiziani, Stefano, Hoang, Trang, and Konopleva, Marina

Published
2020
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18. Inhibition of PIM Kinases in Diffuse Large B-Cell Lymphoma Cells Targets MYC-Dependent Transcriptional Program, Increases CD20 Expression and Augments the Efficacy of Anti-CD20 Antibodies

Author

Szydlowski, Maciej, primary, Garbicz, Filip, additional, Jabłońska, Ewa, additional, Górniak, Patryk, additional, Pyrzynska, Beata, additional, Bojarczuk, Kamil, additional, Komar, Dorota, additional, Prochorec-Sobieszek, Monika, additional, Szumera-Ciećkiewicz, Anna, additional, Rymkiewicz, Grzegorz, additional, Cybulska, Magdalena, additional, Statkiewicz, Małgorzata, additional, Gajewska, Marta, additional, Mikula, MIchał, additional, Golas, Aniela, additional, Domagała, Joanna, additional, Winiarska, Magdalena, additional, Graczyk-Jarzynka, Agnieszka, additional, Bialopiotrowicz, Emilia, additional, Polak, Anna, additional, Barankiewicz, Joanna, additional, Pula, Bartosz, additional, Green, Michael R, additional, Nowis, Dominika, additional, Golab, Jakub, additional, Tomirotti, Andrea Massimiliano, additional, Brzózka, Krzysztof, additional, Pacheco-Blanco, Mariana, additional, Kupcova, Kristyna, additional, Havranek, Ondrej, additional, Chapuy, Bjoern, additional, and Juszczynski, Przemyslaw, additional

Published
2020
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19. Targeting phosphatidylinositol 3 kinase-β and -δ for Bruton tyrosine kinase resistance in diffuse large B-cell lymphoma

Author

Jain, Neeraj, primary, Singh, Satishkumar, additional, Laliotis, Georgios, additional, Hart, Amber, additional, Muhowski, Elizabeth, additional, Kupcova, Kristyna, additional, Chrbolkova, Tereza, additional, Khashab, Tamer, additional, Chowdhury, Sayan Mullick, additional, Sircar, Anuvrat, additional, Shirazi, Fazal, additional, Singh, Ram Kumar, additional, Alinari, Lapo, additional, Zhu, Jiangjiang, additional, Havranek, Ondrej, additional, Tsichlis, Philip, additional, Woyach, Jennifer, additional, Baiocchi, Robert, additional, Samaniego, Felipe, additional, and Sehgal, Lalit, additional

Published
2020
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20. Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma

Author

Prukova, Dana, primary, Andera, Ladislav, additional, Nahacka, Zuzana, additional, Karolova, Jana, additional, Svaton, Michael, additional, Klanova, Magdalena, additional, Havranek, Ondrej, additional, Soukup, Jan, additional, Svobodova, Karla, additional, Zemanova, Zuzana, additional, Tuskova, Diana, additional, Pokorna, Eva, additional, Helman, Karel, additional, Forsterova, Kristina, additional, Pacheco-Blanco, Mariana, additional, Vockova, Petra, additional, Berkova, Adela, additional, Fronkova, Eva, additional, Trneny, Marek, additional, and Klener, Pavel, additional

Published
2019
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21. Co-Targeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Refractory Mantle Cell Lymphoma with Complex Karyotype Changes

Author

Klener, Pavel, primary, Trněný, Marek, additional, Andera, Ladislav, additional, Nahacka, Zuzana, additional, Klanova, Magdalena, additional, Karolova, Jana, additional, Svaton, Michael, additional, Havranek, Ondrej, additional, Soukup, Jan, additional, Zemanova, Zuzana, additional, Tuskova, Diana, additional, Pokorna, Eva, additional, Forsterova, Kristina, additional, Vockova, Petra, additional, Fronkova, Eva, additional, and Prukova, Dana, additional

Published
2018
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24. Molecular Aspects of Tonic B-Cell Receptor Signaling in Diffuse Large B-Cell Lymphoma Provide Biomarkers and Targets for Specific Inhibition

Author

Havranek, Ondrej, primary, Xu, Jingda, additional, Koehrer, Stefan, additional, Wang, Zhiqiang, additional, Comer, Justin M, additional, Becker, Lisa, additional, Yi, Allen F, additional, Burger, Jan A., additional, Westin, Jason R., additional, Zal, Tomasz, additional, and Davis, Richard Eric, additional

Published
2016
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26. B-Cell Receptor Signaling in Diffuse Large B-Cell Lymphoma: Tonic Alone in the Germinal Center B-Cell Subtype, Plus Self Antigen-Induced in the Activated B-Cell Subtype

Author

Havranek, Ondrej, primary, Koehrer, Stefan, additional, Xu, Jingda, additional, Becker, Lisa, additional, Comer, Justin M, additional, Karri, Anusha R, additional, Wang, Zhiqiang, additional, Ma, Wencai, additional, Westin, Jason R, additional, Zal, Tomasz, additional, Burger, Jan A, additional, and Davis, R Eric, additional

Published
2015
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28. Germline multigene panel testing of patients with endometrial cancer.

Author

Kral, Jan, Jelinkova, Sandra, Zemankova, Petra, Vocka, Michal, Borecka, Marianna, Cerna, Leona, Cerna, Marta, Dostalek, Lukas, Duskova, Petra, Foretova, Lenka, Havranek, Ondrej, Horackova, Klara, Hovhannisyan, Milena, Chvojka, Stepan, Kalousova, Marta, Kosarova, Marcela, Koudova, Monika, Krutilkova, Vera, Machackova, Eva, and Nehasil, Petr

Subjects
ENDOMETRIAL cancer, NUCLEOTIDE sequencing, HEREDITARY nonpolyposis colorectal cancer, CANCER patients, GERM cells, GENETIC testing
Abstract

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10−17] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE/POLD1; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria. [ABSTRACT FROM AUTHOR]

Published
2023
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29. Wpływ internalizacji receptora B-komórkowego i jej zahamowania na biologię i przeżycie komórek chłoniaka rozlanego z dużych komórek B (DLBCL).

Author

Górniak, Patryk, Havranek, Ondrej, Polak, Anna, and Juszczyński, Przemysław

Abstract

Copyright of Acta Haematologica Polonica is the property of VM Medica-VM Group (Via Medica) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2022

30. The B-Cell Receptor Is Required for Optimal Viability, Growth, and Chemotherapy Resistance of Diffuse Large B-Cell Lymphoma Cell Lines of the Germinal Center B-Cell Subtype

Author

Havranek, Ondrej, primary, Koehrer, Stefan, additional, Comer, Justin M, additional, Wang, Zhiqiang, additional, Xu, Jingda, additional, Ghosh, Dipanjan, additional, Shinners, Nicholas, additional, Sun, Luhong, additional, Ma, Wencai, additional, Burger, Jan A, additional, and Davis, R Eric, additional

Published
2014
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31. Immunoglobulin Heavy Chain (IgH) Knockout Inhibits Proliferation of Pre-BCR+ B-Cell Acute Lymphoblastic Leukemia (B-ALL) Via a FOXO1 and MYC Dependent Mechanism

Author

Koehrer, Stefan, primary, Havranek, Ondrej, additional, Davis, R Eric, additional, Seyfried, Felix, additional, Coffey, Greg, additional, Kim, Ekaterina, additional, Rosin, Nathalie Y., additional, ten Hacken, Elisa, additional, Jäger, Ulrich, additional, Vanura, Katrina, additional, O'Brien, Susan, additional, Thomas, Deborah A., additional, Kantarjian, Hagop M., additional, Ghosh, Dipanjan, additional, Wang, Zhiqiang, additional, Meyer, Lüder Hinrich, additional, Jumaa, Hassan, additional, and Burger, Jan A., additional

Published
2014
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33. Co-Targeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivoin Relapsed Refractory Mantle Cell Lymphoma with Complex Karyotype Changes

Author

Klener, Pavel, Trněný, Marek, Andera, Ladislav, Nahacka, Zuzana, Klanova, Magdalena, Karolova, Jana, Svaton, Michael, Havranek, Ondrej, Soukup, Jan, Zemanova, Zuzana, Tuskova, Diana, Pokorna, Eva, Forsterova, Kristina, Vockova, Petra, Fronkova, Eva, and Prukova, Dana

Abstract

Introduction

Published
2018
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34. Immunoglobulin Heavy Chain (IgH) Knockout Inhibits Proliferation of Pre-BCR+B-Cell Acute Lymphoblastic Leukemia (B-ALL) Via a FOXO1 and MYC Dependent Mechanism

Author

Koehrer, Stefan, Havranek, Ondrej, Davis, R Eric, Seyfried, Felix, Coffey, Greg, Kim, Ekaterina, Rosin, Nathalie Y., ten Hacken, Elisa, Jäger, Ulrich, Vanura, Katrina, O’Brien, Susan, Thomas, Deborah A., Kantarjian, Hagop M., Ghosh, Dipanjan, Wang, Zhiqiang, Meyer, Lüder Hinrich, Jumaa, Hassan, and Burger, Jan A.

Abstract

A pivotal step during B-cell development is the expression of the precursor B-cell receptor (pre-BCR) by pre-B lymphocytes (cyto-Igµ+, surface-IgM-). The pre-BCR represents an immature form of the BCR and consists of two immunoglobulin heavy chains (IgH), two surrogate light chains (SLC) and the signal transducing adapter proteins Igα and Igβ. A functional pre-BCR drives proliferation of pre-B-cells, ensuring their further differentiation into mature B-cells. By immunophenotype, ~20% of B-cell acute lymphoblastic leukemia (B-ALL) cases originate from the pre-B-cell stage (pre-B-ALL) of lymphocyte development and might therefore also express the pre-BCR. In view of the importance of pre-BCR signaling for normal pre-B-cell development, we hypothesize that it is exploited by pre-B-ALL for malignant growth and proliferation.

Published
2014
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35. Anti-apoptotic MCL1 Protein Represents Critical Survival Molecule for Most Burkitt Lymphomas and BCL2-negative Diffuse Large B-cell Lymphomas.

Author

Klanova M, Kazantsev D, Pokorna E, Zikmund T, Karolova J, Behounek M, Renesova N, Sovilj D, Kelemen CD, Helman K, Jaksa R, Havranek O, Andera L, Trneny M, and Klener P

Subjects
Apoptosis, Burkitt Lymphoma mortality, Cell Line, Tumor, Humans, Lymphoma, Large B-Cell, Diffuse mortality, Burkitt Lymphoma genetics, Lymphoma, Large B-Cell, Diffuse genetics, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism
Abstract

The pro-survival MCL1 protein is overexpressed in many cancers, including B-cell non-Hodgkin lymphomas (B-NHL). S63845 is a highly specific inhibitor of MCL1. We analyzed mechanisms of sensitivity/resistance to S63845 in preclinical models of diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. Annexin V-based cytotoxic assays, Western blot analysis, protein co-immunoprecipitation, and cell clones with manipulated expression of BCL2 family proteins were used to analyze mechanisms of sensitivity to S63845. Experimental in vivo therapy with S63845 and/or venetoclax was performed using patient-derived xenografts (PDX) of treatment-refractory B-NHL. A subset of DLBCL and majority of Burkitt lymphoma cell lines were sensitive to S63845. The level of BCL2 protein expression was the major determinant of resistance to S63845: BCL2 serves as a buffer for pro-apoptotic proteins released from MCL1 upon exposure to S63845. While BCL2-negative lymphomas were effectively eliminated by single-agent S63845, its combination with venetoclax was synthetically lethal in BCL2-positive PDX models. Concerning MCL1, both, the level of MCL1 protein expression, and its occupational status represent key factors mediating sensitivity to S63845. In contrast to MCL1-BIM/BAK1 complexes that prime lymphoma cells for S63845-mediated apoptosis, MCL1-NOXA complexes are associated with S63845 resistance. In conclusion, MCL1 represents a critical survival molecule for most Burkitt lymphomas and a subset of BCL2-negative DLBCLs. The level of BCL2 and MCL1 expression and occupational status of MCL1 belong to the key modulators of sensitivity/resistance to S63845. Co-treatment with venetoclax can overcome BCL2-mediated resistance to S63845, and enhance efficacy of MCL1 inhibitors in BCL2-positive aggressive B-NHL., (©2021 The Authors; Published by the American Association for Cancer Research.)

Published
2022
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36. Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs.

Author

Mathur R, Sehgal L, Havranek O, Köhrer S, Khashab T, Jain N, Burger JA, Neelapu SS, Davis RE, and Samaniego F

Subjects
Antineoplastic Agents therapeutic use, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Drug Resistance, Neoplasm genetics, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Jumonji Domain-Containing Histone Demethylases genetics, Jumonji Domain-Containing Histone Demethylases metabolism, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse mortality, Prognosis, Receptors, Antigen, B-Cell metabolism, Signal Transduction drug effects, Antineoplastic Agents pharmacology, Benzazepines pharmacology, Jumonji Domain-Containing Histone Demethylases antagonists & inhibitors, Lymphoma, Large B-Cell, Diffuse metabolism, Pyrimidines pharmacology
Abstract

Histone methylation and demethylation regulate B-cell development, and their deregulation correlates with tumor chemoresistance in diffuse large B-cell lymphoma, limiting cure rates. Since histone methylation status correlates with disease aggressiveness and relapse, we investigated the therapeutic potential of inhibiting histone 3 Lys27 demethylase KDM6B, in vitro, using the small molecule inhibitor GSK-J4. KDM6B is overexpressed in the germinal center B-cell subtype of diffuse large B-cell lymphoma, and higher KDM6B levels are associated with worse survival in patients with diffuse large B-cell lymphoma treated with R-CHOP. GSK-J4-induced apoptosis was observed in five (SU-DHL-6, OCI-Ly1, Toledo, OCI-Ly8, SU-DHL-8) out of nine germinal center B-cell diffuse large B-cell lymphoma cell lines. Treatment with GSK-J4 predominantly resulted in downregulation of B-cell receptor signaling and BCL6. Cell lines expressing high BCL6 levels or CREBBP/EP300 mutations were sensitive to GSK-J4. Our results suggest that B-cell receptor-dependent downregulation of BCL6 is responsible for GSK-J4-induced cytotoxicity. Furthermore, GSK-J4-mediated inhibition of KDM6B sensitizes germinal center B-cell diffuse large B-cell lymphoma cells to chemotherapy agents that are currently utilized in treatment regimens for diffuse large B-cell lymphoma., (Copyright© Ferrata Storti Foundation.)

Published
2017
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37. Is there an intermediate-risk non-seminoma? long-term treatment results from a single center.

Author

Cvek J, Feltl D, Hajek J, Jackaninova J, Ruzickova K, Havranek O, Dvorackova J, and Dobes P

Subjects
Adolescent, Adult, Aged, Combined Modality Therapy, Humans, Male, Middle Aged, Neoplasm Staging, Neoplasms, Germ Cell and Embryonal mortality, Neoplasms, Germ Cell and Embryonal pathology, Retrospective Studies, Risk, Testicular Neoplasms mortality, Testicular Neoplasms pathology, Neoplasms, Germ Cell and Embryonal therapy, Testicular Neoplasms therapy
Abstract

Purpose: We retrospectively assessed the treatment results of patients with testicular non-seminoma to evaluate possible predictive and prognostic factors., Methods: 189 patients with testicular non-seminoma treated between 2000 and 2012 were retrospectively evaluated. Treatment was based on orchiectomy plus chemotherapy (bleomycin/etoposide/cisplatin and vinblastine/ifosfamide/ cisplatin); retroperitoneal lymphadenectomy was only performed for residual disease after chemotherapy. The treatment protocol was updated regularly according to international standards. Overall survival (OS) was evaluated with the Kaplan-Meier method at a significance level of 5% according to stage, Karnofsky performance status (KPS), and chemotherapy dose intensity., Results: OS differed significantly for patients at different TNM stages (p=0.000); however, detailed analysis revealed significantly worse survival only in stage IIIC (10-year OS for IIIC vs IIIA+B, 35 vs 88%, p=0.001), while the difference between IIIB and lower stages was not significant (p=0.383). Patients with no chemotherapy dose reduction had significantly higher OS than those with any kind of dose reduction (10-year OS 96 vs 0%, p=0.000). For stage IIIC disease, however, dose intensity had no influence on OS (p=0.167). KPS had no prognostic significance for OS (KPS<80 vs ≥80, p=0.627) for stage IIIA+B and for stage IIIC., Conclusion: The standard of care for testicular non-seminoma offers excellent prognosis with no significant differences in OS for good- and intermediate-risk patients. Reduction of chemotherapy dose negatively impacted OS in patients with stage IIIA+B and thus should be avoided.

Published
2014

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