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21 results on '"van Herk, Stanley"'

1. 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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2. 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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3. 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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4. 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., Hollestelle, Antoinette, 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

Abstract

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.

Published
2024

5. 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., Schneider, Rebekka K., 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.

Abstract

It is still not fully understood how genetic haploinsufficiency in del(5q) myelodysplastic syndrome (MDS) contributes to malignant transformation of hematopoietic stem cells. We asked how compound haploinsufficiency for Csnk1a1 and Egr1 in the common deleted region on chromosome 5 affects hematopoietic stem cells. Additionally, Trp53 was disrupted as the most frequently comutated gene in del(5q) MDS using CRISPR/Cas9 editing in hematopoietic progenitors of wild-type (WT), Csnk1a1–/+, Egr1–/+, Csnk1a1/Egr1–/+ mice. A transplantable acute leukemia only developed in the Csnk1a1–/+ Trp53–edited recipient. Isolated blasts were indefinitely cultured ex vivo and gave rise to leukemia after transplantation, providing a tool to study disease mechanisms or perform drug screenings. In a small-scale drug screening, the collaborative effect of Csnk1a1 haploinsufficiency and Trp53 sensitized blasts to the CSNK1 inhibitor A51 relative to WT or Csnk1a1 haploinsufficient cells. In vivo, A51 treatment significantly reduced blast counts in Csnk1a1 haploinsufficient/Trp53 acute leukemias and restored hematopoiesis in the bone marrow. Transcriptomics on blasts and their normal counterparts showed that the derived leukemia was driven by MAPK and Myc upregulation downstream of Csnk1a1 haploinsufficiency cooperating with a downregulated p53 axis. A collaborative effect of Csnk1a1 haploinsufficiency and p53 loss on MAPK and Myc upregulation was confirmed on the protein level. Downregulation of Myc protein expression correlated with efficient elimination of blasts in A51 treatment. The “Myc signature” closely resembled the transcriptional profile of patients with del(5q) MDS with TP53 mutation.

Published
2024

6. 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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8. 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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9. 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. Allele-specific expression of GATA2 due to epigenetic dysregulation in CEBPA double-mutant AML

Author

Cancer, CMM Groep De Ridder, CMM, 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, Wouters, Bas J., Cancer, CMM Groep De Ridder, CMM, 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.

Published
2021

12. 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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13. 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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14. 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. 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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17. 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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18. 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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19. 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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21. Functional Homologous Recombination (HR) Screening Shows the Majority of BRCA1/2 -Mutant Breast and Ovarian Cancer Cell Lines Are HR-Proficient.

Author

Meijer TG, Martens JWM, Prager-van der Smissen WJC, Verkaik NS, Beaufort CM, van Herk S, Robert-Finestra T, Hoogenboezem RM, Ruigrok-Ritstier K, Paul MW, Gribnau J, Bindels EMJ, Kanaar R, Jager A, van Gent DC, and Hollestelle A

Abstract

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.

Published
2024
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