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18 results on '"van Herk, Stanley"'

1. STAG2 mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia

Author

Fischer, Alexander, Hernández-Rodríguez, Benjamín, Mulet-Lazaro, Roger, Nuetzel, Margit, Hölzl, Fabian, van Herk, Stanley, Kavelaars, François G., Stanewsky, Hanna, Ackermann, Ute, Niang, Amadou H., Diaz, Noelia, Reuschel, Edith, Strieder, Nicholas, Hernández-López, Inmaculada, Valk, Peter J.M., Vaquerizas, Juan M., Rehli, Michael, Delwel, Ruud, and Gebhard, Claudia

Published
2024
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2. Collaborative effect of Csnk1a1 haploinsufficiency and mutant p53 in Myc induction can promote leukemic transformation

Author

Fuchs, Stijn N. R., Stalmann, Ursula S. A., Snoeren, Inge A. M., Bindels, Eric, Schmitz, Stephani, Banjanin, Bella, Hoogenboezem, Remco M., van Herk, Stanley, Saad, Mohamed, Walter, Wencke, Haferlach, Torsten, Seillier, Lancelot, Saez-Rodriguez, Julio, Dugourd, Aurélien J. F., Lehmann, Kjong-Van, Ben-Neriah, Yinon, Gleitz, Hélène F. E., and Schneider, Rebekka K.

Published
2024
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3. Epigenetic alterations affecting hematopoietic regulatory networks as drivers of mixed myeloid/lymphoid leukemia

Author

Mulet-Lazaro, Roger, van Herk, Stanley, Nuetzel, Margit, Sijs-Szabo, Aniko, Díaz, Noelia, Kelly, Katherine, Erpelinck-Verschueren, Claudia, Schwarzfischer-Pfeilschifter, Lucia, Stanewsky, Hanna, Ackermann, Ute, Glatz, Dagmar, Raithel, Johanna, Fischer, Alexander, Pohl, Sandra, Rijneveld, Anita, Vaquerizas, Juan M., Thiede, Christian, Plass, Christoph, Wouters, Bas J., Delwel, Ruud, Rehli, Michael, and Gebhard, Claudia

Published
2024
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4. Collaborative effect of Csnk1a1 haploinsufficiency and mutant p53 in Myc induction can promote leukemic transformation

Author

Fuchs, Stijn N.R, primary, Stalmann, Ursula S A, additional, Snoeren, Inge A.M, additional, Bindels, Eric, additional, Schmitz, Stephani, additional, Banjanin, Bella, additional, Hoogenboezem, Remco, additional, van Herk, Stanley, additional, Saad, Mohamed, additional, Walter, Wencke, additional, Haferlach, Torsten, additional, Seillier, Lancelot, additional, Saez-Rodriguez, Julio, additional, Dugourd, Aurelien J.F., additional, Lehmann, Kjong-Van, additional, Ben-Neriah, Y, additional, Gleitz, Hélène F.E, additional, and Schneider, Rebekka K, additional

Published
2023
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6. Functional Homologous Recombination (HR) Screening Shows the Majority of BRCA1/2 -Mutant Breast and Ovarian Cancer Cell Lines Are HR-Proficient.

Author

Meijer, Titia G., Martens, John W. M., Prager-van der Smissen, Wendy J. C., Verkaik, Nicole S., Beaufort, Corine M., van Herk, Stanley, Robert-Finestra, Teresa, Hoogenboezem, Remco M., Ruigrok-Ritstier, Kirsten, Paul, Maarten W., Gribnau, Joost, Bindels, Eric M. J., Kanaar, Roland, Jager, Agnes, van Gent, Dik C., and Hollestelle, Antoinette

Subjects
OVARIAN tumors, GENETIC mutation, HOMOGRAFTS, SEQUENCE analysis, BRCA genes, FUNCTIONAL status, EARLY detection of cancer, CELLS, GENE expression profiling, DESCRIPTIVE statistics, METHYLATION, RESEARCH funding, CELL lines, BREAST tumors
Abstract

Simple Summary: Cancer cells from patients who carry a disease-causing BRCA1 or BRCA2 mutation are incapable of repairing double-strand DNA breaks via the homologous recombination (HR) repair pathway. As a consequence, these patients respond to platinum-based chemotherapy and Poly-[ADP-Ribose]-Polymerase inhibitors (PARPi). However, using a functional read-out for HR, we show that not all HR-deficient cell lines carry a BRCA1/2 mutation. Moreover, the majority of BRCA1/2-mutant cell lines are HR proficient, highlighting the importance of measuring the functional HR status. For almost all of the BRCA1/2-mutant HR proficient cell lines, we could explain the discrepant HR status. The observed reversion mechanisms predominantly acted on restoring the BRCA1 or BRCA2 mutation directly. Taken together, our results indicate that only determining BRCA1/2 mutation status may not suffice for selecting patients for platinum-based chemotherapy or PARPi. Moreover, for experimental approaches cell line functionality of HR should be assessed beforehand. Tumors with a pathogenic BRCA1/2 mutation are homologous recombination (HR)-deficient (HRD) and consequently sensitive to platinum-based chemotherapy and Poly-[ADP-Ribose]-Polymerase inhibitors (PARPi). We hypothesized that functional HR status better reflects real-time HR status than BRCA1/2 mutation status. Therefore, we determined the functional HR status of 53 breast cancer (BC) and 38 ovarian cancer (OC) cell lines by measuring the formation of RAD51 foci after irradiation. Discrepancies between functional HR and BRCA1/2 mutation status were investigated using exome sequencing, methylation and gene expression data from 50 HR-related genes. A pathogenic BRCA1/2 mutation was found in 10/53 (18.9%) of BC and 7/38 (18.4%) of OC cell lines. Among BRCA1/2-mutant cell lines, 14/17 (82.4%) were HR-proficient (HRP), while 1/74 (1.4%) wild-type cell lines was HRD. For most (80%) cell lines, we explained the discrepancy between functional HR and BRCA1/2 mutation status. Importantly, 12/14 (85.7%) BRCA1/2-mutant HRP cell lines were explained by mechanisms directly acting on BRCA1/2. Finally, functional HR status was strongly associated with COSMIC single base substitution signature 3, but not BRCA1/2 mutation status. Thus, the majority of BRCA1/2-mutant cell lines do not represent a suitable model for HRD. Moreover, exclusively determining BRCA1/2 mutation status may not suffice for platinum-based chemotherapy or PARPi patient selection. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Cohesin-STAG2 Mutations Alter Chromatin Structure and Gene Regulation in Human Acute Myeloid Leukemia

Author

Fischer, Alexander, primary, Mulet-Lazaro, Roger, additional, Nützel, Margit, additional, van Herk, Stanley, additional, Stanewsky, Hanna, additional, Ackermann, Ute, additional, Reuschel, Edith, additional, Strieder, Nicholas, additional, Hernandez-Lopez, Inmaculada, additional, Herr, Wolfgang, additional, Valk, Peter J.M., additional, Rehli, Michael, additional, Delwel, Ruud, additional, and Gebhard, Claudia, additional

Published
2022
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8. Oncogene EVI1 Drives Acute Myeloid Leukemia Via a Targetable EVI1-CtBP1/2 Interaction and By Repressing Myeloid Regulator CEBPA

Author

Pastoors, Dorien, primary, Havermans, Marije, additional, Hoogenboezem, Remco, additional, Mulet-Lazaro, Roger, additional, Brian, Duncan, additional, Smeenk, Leonie, additional, Erpelinck-Verschueren, Claudia, additional, van Herk, Stanley, additional, Wouters, Bas, additional, Demmers, Jeroen A.A., additional, Zuber, Johannes, additional, Enver, Tariq, additional, Groen, Richard WJ, additional, Bindels, Eric, additional, and Delwel, Ruud, additional

Published
2022
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10. Selective Requirement of MYB for Oncogenic Hyperactivation of a Translocated Enhancer in Leukemia

Author

Smeenk, Leonie, primary, Ottema, Sophie, additional, Mulet-Lazaro, Roger, additional, Ebert, Anja, additional, Havermans, Marije, additional, Varea, Andrea Arricibita, additional, Fellner, Michaela, additional, Pastoors, Dorien, additional, van Herk, Stanley, additional, Erpelinck-Verschueren, Claudia, additional, Grob, Tim, additional, Hoogenboezem, Remco M., additional, Kavelaars, François G., additional, Matson, Daniel R., additional, Bresnick, Emery H., additional, Bindels, Eric M., additional, Kentsis, Alex, additional, Zuber, Johannes, additional, and Delwel, Ruud, additional

Published
2021
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11. Allele-specific expression of GATA2 due to epigenetic dysregulation in CEBPA double-mutant AML

Author

Mulet-Lazaro, Roger, primary, van Herk, Stanley, additional, Erpelinck, Claudia, additional, Bindels, Eric, additional, Sanders, Mathijs A., additional, Vermeulen, Carlo, additional, Renkens, Ivo, additional, Valk, Peter, additional, Melnick, Ari M., additional, de Ridder, Jeroen, additional, Rehli, Michael, additional, Gebhard, Claudia, additional, Delwel, Ruud, additional, and Wouters, Bas J., additional

Published
2021
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12. STAG2mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia

Author

Fischer, Alexander, Hernández-Rodríguez, Benjamín, Mulet-Lazaro, Roger, Nuetzel, Margit, Hölzl, Fabian, van Herk, Stanley, Kavelaars, François G., Stanewsky, Hanna, Ackermann, Ute, Niang, Amadou H., Diaz, Noelia, Reuschel, Edith, Strieder, Nicholas, Hernández-López, Inmaculada, Valk, Peter J.M., Vaquerizas, Juan M., Rehli, Michael, Delwel, Ruud, and Gebhard, Claudia

Abstract

Cohesin shapes the chromatin architecture, including enhancer-promoter interactions. Its components, especially STAG2, but not its paralog STAG1, are frequently mutated in myeloid malignancies. To elucidate the underlying mechanisms of leukemogenesis, we comprehensively characterized genetic, transcriptional, and chromatin conformational changes in acute myeloid leukemia (AML) patient samples. Specific loci displayed altered cohesin occupancy, gene expression, and local chromatin activation, which were not compensated by the remaining STAG1-cohesin. These changes could be linked to disrupted spatial chromatin looping in cohesin-mutated AMLs. Complementary depletion of STAG2 or STAG1 in primary human hematopoietic progenitors (HSPCs) revealed effects resembling STAG2-mutant AML-specific changes following STAG2 knockdown, not invoked by the depletion of STAG1. STAG2-deficient HSPCs displayed impaired differentiation capacity and maintained HSPC-like gene expression. This work establishes STAG2 as a key regulator of chromatin contacts, gene expression, and differentiation in the hematopoietic system and identifies candidate target genes that may be implicated in human leukemogenesis.

Published
2024
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13. Atypical 3q26/MECOM rearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia

Author

Ottema, Sophie, primary, Mulet-Lazaro, Roger, primary, Beverloo, H. Berna, primary, Erpelinck, Claudia, primary, van Herk, Stanley, primary, van der Helm, Robert, primary, Havermans, Marije, primary, Grob, Tim, primary, Valk, Peter J. M., primary, Bindels, Eric, primary, Haferlach, Torsten, primary, Haferlach, Claudia, primary, Smeenk, Leonie, primary, and Delwel, Ruud, primary

Published
2020
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15. Integrated Analysis of Global DNA Methylation and Transcription Reveals a Leukemia Subtype with Extreme Hypermethylation Associated with Silencing of Regulators of Differentiation

Author

Gebhard, Claudia, primary, Mulet-Lazaro, Roger, additional, Schwarzfischer, Lucia, additional, Glatz, Dagmar, additional, Nuetzel, Margit, additional, Heudobler, Daniel, additional, Pohl, Sandra, additional, Herr, Wolfgang, additional, Ehninger, Gerhard, additional, Erpelinck-Verschueren, Claudia, additional, van Herk, Stanley, additional, Wouters, B.J., additional, Thiede, Christian, additional, Delwel, Ruud, additional, and Rehli, Michael, additional

Published
2018
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16. Allele-specific expression of GATA2due to epigenetic dysregulation in CEBPAdouble-mutant AML

Author

Mulet-Lazaro, Roger, van Herk, Stanley, Erpelinck, Claudia, Bindels, Eric, Sanders, Mathijs A., Vermeulen, Carlo, Renkens, Ivo, Valk, Peter, Melnick, Ari M., de Ridder, Jeroen, Rehli, Michael, Gebhard, Claudia, Delwel, Ruud, and Wouters, Bas J.

Abstract

Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid- or cancer-related gene. GATA2ASE was strongly associated with CEBPAdouble mutations (DMs), with 95% of cases presenting GATA2ASE. In CEBPADM AML with GATA2mutations, the mutated allele was preferentially expressed. We found that GATA2ASE was a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPADM AML. Acquisition of GATA2ASE involved silencing of 1 allele via promoter methylation and concurrent overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission along with GATA2ASE. In summary, we propose that GATA2ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPADMs. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.

Published
2021
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17. Atypical 3q26/MECOMrearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia

Author

Ottema, Sophie, Mulet-Lazaro, Roger, Beverloo, H. Berna, Erpelinck, Claudia, van Herk, Stanley, van der Helm, Robert, Havermans, Marije, Grob, Tim, Valk, Peter J.M., Bindels, Eric, Haferlach, Torsten, Haferlach, Claudia, Smeenk, Leonie, and Delwel, Ruud

Abstract

Acute myeloid leukemia (AML) with inv(3)/t(3;3)(q21q26) is a distinct World Health Organization recognized entity, characterized by its aggressive course and poor prognosis. In this subtype of AML, the translocation of a GATA2enhancer (3q21) to MECOM(3q26) results in overexpression of the MECOMisoform EVI1and monoallelic expression of GATA2from the unaffected allele. The full-length MECOMtranscript, MDS1-EVI1, is not expressed as the result of the 3q26 rearrangement. Besides the classical inv(3)/t(3;3), a number of other 3q26/MECOMrearrangements with poor treatment response have been reported in AML. Here, we demonstrate, in a group of 33 AML patients with atypical 3q26 rearrangements, MECOMinvolvement with EVI1overexpression but no or low MDS1-EVI1levels. Moreover, the 3q26 translocations in these AML patients often involve superenhancers of genes active in myeloid development (eg, CD164, PROM1, CDK6, or MYC). In >50% of these cases, allele-specific GATA2expression was observed, either by copy-number loss or by an unexplained allelic imbalance. Altogether, atypical 3q26 recapitulate the main leukemic mechanism of inv(3)/t(3;3) AML, namely EVI1overexpression driven by enhancer hijacking, absent MDS1-EVI1expression and potential GATA2involvement. Therefore, we conclude that both atypical 3q26/MECOMand inv(3)/t(3;3) can be classified as a single entity of 3q26-rearranged AMLs. Routine analyses determining MECOMrearrangements and EVI1and MDS1-EVI1expression are required to recognize 3q-rearranged AML cases.

Published
2020
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