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Your search keyword '"Zammarchi, Francesca"' showing total 4 results
Start Over Author "Zammarchi, Francesca" Topic lymphoma, large-cell, anaplastic
4 results on '"Zammarchi, Francesca"'

1. Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.

Author

Liang HC, Costanza M, Prutsch N, Zimmerman MW, Gurnhofer E, Montes-Mojarro IA, Abraham BJ, Prokoph N, Stoiber S, Tangermann S, Lobello C, Oppelt J, Anagnostopoulos I, Hielscher T, Pervez S, Klapper W, Zammarchi F, Silva DA, Garcia KC, Baker D, Janz M, Schleussner N, Fend F, Pospíšilová Š, Janiková A, Wallwitz J, Stoiber D, Simonitsch-Klupp I, Cerroni L, Pileri S, de Leval L, Sibon D, Fataccioli V, Gaulard P, Assaf C, Knörr F, Damm-Welk C, Woessmann W, Turner SD, Look AT, Mathas S, Kenner L, and Merkel O

Subjects
Animals, Basic-Leucine Zipper Transcription Factors metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Gene Expression Regulation, Neoplastic, Humans, Immunoconjugates pharmacology, Interleukin-15 pharmacology, Interleukin-2 pharmacology, Interleukin-2 Receptor alpha Subunit genetics, Interleukin-2 Receptor alpha Subunit immunology, Interleukin-2 Receptor alpha Subunit metabolism, Ki-1 Antigen genetics, Ki-1 Antigen metabolism, Lymphoma, Large-Cell, Anaplastic drug therapy, Lymphoma, Large-Cell, Anaplastic metabolism, Lymphoma, Large-Cell, Anaplastic pathology, Mice, Receptors, Interleukin-2 immunology, Receptors, Interleukin-2 metabolism, Regulatory Sequences, Nucleic Acid, Repressor Proteins metabolism, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Basic-Leucine Zipper Transcription Factors genetics, Lymphoma, Large-Cell, Anaplastic genetics, Receptors, Interleukin-2 genetics, Repressor Proteins genetics
Abstract

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL., (© 2021. The Author(s).)

Published
2021
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2. The Role of Specific ATP-Binding Cassette Transporters in the Acquired Resistance to Pyrrolobenzodiazepine Dimer-Containing Antibody-Drug Conjugates.

Author

Corbett S, Huang S, Zammarchi F, Howard PW, van Berkel PH, and Hartley JA

Subjects
ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics, ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, Antibodies, Monoclonal, Humanized chemistry, Antibodies, Monoclonal, Humanized pharmacology, Benzodiazepines pharmacology, Cell Line, Tumor, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Immunoconjugates chemistry, Lymphoma, Large-Cell, Anaplastic drug therapy, Lymphoma, Large-Cell, Anaplastic metabolism, Multidrug Resistance-Associated Protein 2, Multidrug Resistance-Associated Proteins genetics, Multidrug Resistance-Associated Proteins metabolism, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Stomach Neoplasms drug therapy, Stomach Neoplasms metabolism, Benzodiazepines chemistry, Drug Resistance, Neoplasm, Immunoconjugates pharmacology, Lymphoma, Large-Cell, Anaplastic genetics, Pyrroles chemistry, Stomach Neoplasms genetics
Abstract

Antibody-drug conjugates (ADC) containing pyrrolobenzodiazepine (PBD) dimers are being evaluated clinically in both hematologic and solid tumors. These include ADCT-301 (camidanlumab tesirine) and ADCT-402 (loncastuximab tesirine) in pivotal phase II trials that contain the payload tesirine, which releases the PBD dimer warhead SG3199. An important consideration in future clinical development is acquired resistance. The aim was to generate and characterize PBD acquired resistant cell lines in both hematologic and solid tumor settings. Human Karpas-299 (ALCL) and NCI-N87 (gastric cancer) cells were incubated with increasing IC 50 doses of ADC (targeting CD25 and HER2, respectively) or SG3199 in a pulsed manner until stable acquired resistance was established. The level of resistance achieved was approximately 3,000-fold for ADCT-301 and 3-fold for SG3199 in Karpas-299, and 8-fold for ADCT-502 and 4-fold for SG3199 in NCI-N87. Cross-resistance between ADC and SG3199, and with an alternative PBD-containing ADC or PBD dimer was observed. The acquired resistant lines produced fewer DNA interstrand cross-links, indicating an upstream mechanism of resistance. Loss of antibody binding or internalization was not observed. A human drug transporter PCR Array revealed several genes upregulated in all the resistant cell lines, including ABCG2 and ABCC2 , but not ABCB1 ( MDR1 ). These findings were confirmed by RT-PCR and Western blot, and inhibitors and siRNA knockdown of ABCG2 and ABCC2 recovered drug sensitivity. These data show that acquired resistance to PBD-ADCs and SG3199 can involve specific ATP-binding cassette drug transporters. This has clinical implications as potential biomarkers of resistance and for the rational design of drug combinations., (©2020 American Association for Cancer Research.)

Published
2020
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3. Super-enhancer-based identification of a BATF3/IL-2R−module reveals vulnerabilities in anaplastic large cell lymphoma

Author

Liang, Huan-Chang, Costanza, Mariantonia, Prutsch, Nicole, Zimmerman, Mark W., Gurnhofer, Elisabeth, Montes-Mojarro, Ivonne A., Abraham, Brian J., Prokoph, Nina, Stoiber, Stefan, Tangermann, Simone, Lobello, Cosimo, Oppelt, Jan, Anagnostopoulos, Ioannis, Hielscher, Thomas, Pervez, Shahid, Klapper, Wolfram, Zammarchi, Francesca, Silva, Daniel-Adriano, Garcia, K. Christopher, Baker, David, Janz, Martin, Schleussner, Nikolai, Fend, Falko, Pospíšilová, Šárka, Janiková, Andrea, Wallwitz, Jacqueline, Stoiber, Dagmar, Simonitsch-Klupp, Ingrid, Cerroni, Lorenzo, Pileri, Stefano, de Leval, Laurence, Sibon, David, Fataccioli, Virginie, Gaulard, Philippe, Assaf, Chalid, Knörr, Fabian, Damm-Welk, Christine, Woessmann, Wilhelm, Turner, Suzanne D., Look, A. Thomas, Mathas, Stephan, Kenner, Lukas, Merkel, Olaf, Liang, Huan-Chang [0000-0003-2612-3714], Costanza, Mariantonia [0000-0002-8959-1083], Zimmerman, Mark W. [0000-0003-2489-3889], Montes-Mojarro, Ivonne A. [0000-0003-0636-7623], Abraham, Brian J. [0000-0001-8085-3027], Prokoph, Nina [0000-0002-6429-9895], Stoiber, Stefan [0000-0003-3293-867X], Oppelt, Jan [0000-0002-3076-4840], Klapper, Wolfram [0000-0001-7208-4117], Silva, Daniel-Adriano [0000-0002-3195-9009], Garcia, K. Christopher [0000-0001-9273-0278], Baker, David [0000-0001-7896-6217], Janz, Martin [0000-0002-1127-0044], Fend, Falko [0000-0002-5496-293X], de Leval, Laurence [0000-0003-3994-516X], Turner, Suzanne D. [0000-0002-8439-4507], Look, A. Thomas [0000-0001-7851-8617], Mathas, Stephan [0000-0001-9626-1413], Kenner, Lukas [0000-0003-2184-1338], Merkel, Olaf [0000-0001-5089-344X], Apollo - University of Cambridge Repository, Zimmerman, Mark W [0000-0003-2489-3889], Montes-Mojarro, Ivonne A [0000-0003-0636-7623], Abraham, Brian J [0000-0001-8085-3027], Garcia, K Christopher [0000-0001-9273-0278], Turner, Suzanne D [0000-0002-8439-4507], and Look, A Thomas [0000-0001-7851-8617]

Subjects
CRISPR-Cas9 genome editing, Cancer Research, Immunoconjugates, Cell Survival, Science, Ki-1 Antigen, Regulatory Sequences, Nucleic Acid, 631/67/1990/291/1621/1916, 38/91, 96/95, Mice, Cell Line, Tumor, hemic and lymphatic diseases, Animals, Humans, Cell Proliferation, Interleukin-15, High-throughput screening, Interleukin-2 Receptor alpha Subunit, article, Receptors, Interleukin-2, Basic-Leucine Zipper Transcription Factors/genetics, Basic-Leucine Zipper Transcription Factors/metabolism, Cell Proliferation/drug effects, Cell Survival/drug effects, Gene Expression Regulation, Neoplastic, Immunoconjugates/pharmacology, Interleukin-15/pharmacology, Interleukin-2/pharmacology, Interleukin-2 Receptor alpha Subunit/genetics, Interleukin-2 Receptor alpha Subunit/immunology, Interleukin-2 Receptor alpha Subunit/metabolism, Ki-1 Antigen/genetics, Ki-1 Antigen/metabolism, Lymphoma, Large-Cell, Anaplastic/drug therapy, Lymphoma, Large-Cell, Anaplastic/genetics, Lymphoma, Large-Cell, Anaplastic/metabolism, Lymphoma, Large-Cell, Anaplastic/pathology, Receptors, Interleukin-2/genetics, Receptors, Interleukin-2/immunology, Receptors, Interleukin-2/metabolism, Repressor Proteins/genetics, Repressor Proteins/metabolism, Signal Transduction/drug effects, Xenograft Model Antitumor Assays, 45/15, 96/21, Repressor Proteins, 631/337/4041/3196, Mechanisms of disease, Basic-Leucine Zipper Transcription Factors, Interleukin-2, Lymphoma, Large-Cell, Anaplastic, T-cell lymphoma, 631/1647/2163, 631/80/304, 82/51, Signal Transduction
Abstract

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL., Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma often with poor prognosis. To identify genes defining ALCL cell state and dependencies, the authors here characterize ALCL-specific super-enhancers and describe the BATF3/IL-2R−module as a therapeutic opportunity for ALCL.

Published
2021

4. Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma

Author

Liang, Huan-Chang, Costanza, Mariantonia, Prutsch, Nicole, Zimmerman, Mark W, Gurnhofer, Elisabeth, Montes-Mojarro, Ivonne A, Abraham, Brian J, Prokoph, Nina, Stoiber, Stefan, Tangermann, Simone, Lobello, Cosimo, Oppelt, Jan, Anagnostopoulos, Ioannis, Hielscher, Thomas, Pervez, Shahid, Klapper, Wolfram, Zammarchi, Francesca, Silva, Daniel-Adriano, Garcia, K Christopher, Baker, David, Janz, Martin, Schleussner, Nikolai, Fend, Falko, Pospíšilová, Šárka, Janiková, Andrea, Wallwitz, Jacqueline, Stoiber, Dagmar, Simonitsch-Klupp, Ingrid, Cerroni, Lorenzo, Pileri, Stefano, De Leval, Laurence, Sibon, David, Fataccioli, Virginie, Gaulard, Philippe, Assaf, Chalid, Knörr, Fabian, Damm-Welk, Christine, Woessmann, Wilhelm, Turner, Suzanne D, Look, A Thomas, Mathas, Stephan, Kenner, Lukas, and Merkel, Olaf

Subjects
Interleukin-15, Immunoconjugates, Cell Survival, Interleukin-2 Receptor alpha Subunit, Ki-1 Antigen, Receptors, Interleukin-2, Regulatory Sequences, Nucleic Acid, Xenograft Model Antitumor Assays, 3. Good health, Gene Expression Regulation, Neoplastic, Repressor Proteins, Mice, Basic-Leucine Zipper Transcription Factors, hemic and lymphatic diseases, Cell Line, Tumor, Animals, Humans, Interleukin-2, Lymphoma, Large-Cell, Anaplastic, Cell Proliferation, Signal Transduction
Abstract

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.

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