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207. Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia

Author

Vadakekolathu, Jayakumar, primary, Minden, Mark D., additional, Hood, Tressa, additional, Church, Sarah E., additional, Reeder, Stephen, additional, Altmann, Heidi, additional, Sullivan, Amy H., additional, Viboch, Elena, additional, Patel, Tasleema, additional, Ibrahimova, Narmin, additional, Warren, Sarah E., additional, Arruda, Andrea, additional, Liang, Yan, additional, Muth, John, additional, Schmitz, Marc, additional, Cesano, Alessandra, additional, Pockley, A. Graham, additional, Valk, Peter J.M., additional, Löwenberg, Bob, additional, Bornhäuser, Martin, additional, Tasian, Sarah K., additional, Rettig, Michael P., additional, Davidson-Moncada, Jan, additional, DiPersio, John F., additional, and Rutella, Sergio, additional

Published
2019
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210. CD34+CD38− leukemic stem cell frequency to predict outcome in acute myeloid leukemia

Author

Zeijlemaker, Wendelien, primary, Grob, Tim, additional, Meijer, Rosa, additional, Hanekamp, Diana, additional, Kelder, Angèle, additional, Carbaat-Ham, Jannemieke C., additional, Oussoren-Brockhoff, Yvonne J. M., additional, Snel, Alexander N., additional, Veldhuizen, Dennis, additional, Scholten, Willemijn J., additional, Maertens, Johan, additional, Breems, Dimitri A., additional, Pabst, Thomas, additional, Manz, Markus G., additional, van der Velden, Vincent H. J., additional, Slomp, Jennichjen, additional, Preijers, Frank, additional, Cloos, Jacqueline, additional, van de Loosdrecht, Arjan A., additional, Löwenberg, Bob, additional, Valk, Peter J. M., additional, Jongen-Lavrencic, Mojca, additional, Ossenkoppele, Gert J., additional, and Schuurhuis, Gerrit J., additional

Published
2018
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211. Complex 3q26/EVI1 Rearrangements Genocopy Inv(3)/t(3;3) Acute Myeloid Leukemias By Enhancer Hijacking, EVI1 Overexpression, Absent MDS1-EVI1 and Low GATA2 Expression

Author

Ottema, Sophie, primary, Mulet-Lazaro, Roger, additional, Beverloo, Berna, additional, Havermans, Marije, additional, Erpelinck-Verschueren, Claudia, additional, Grob, Tim, additional, Valk, Peter, additional, Bindels, Eric, additional, Haferlach, Torsten, additional, Haferlach, Claudia, additional, Smeenk, Leonie, additional, and Delwel, Ruud, additional

Published
2018
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212. Whole Transcriptome RNA Sequencing As a Comprehensive Diagnostic Tool for Acute Myeloid Leukemia

Author

Griffioen, Marieke, primary, Arindrarto, Wibowo, additional, Borras, Daniel M., additional, Locher, Irene J., additional, van Diessen, Saskia A.M.E., additional, van der Holst, Rosalie, additional, van der Meijden, Edith D., additional, Honders, M. Willy, additional, de Leeuw, Rick H., additional, Jedema, Inge, additional, Kroes, Wilma G.M., additional, Knijnenburg, Jeroen, additional, Vermaat, Joost, additional, Valk, Peter, additional, Janssen, Bart, additional, de Knijff, Peter, additional, van Bergen, Cornelis A.M., additional, van den Akker, Erik B., additional, 't Hoen, Peter A.C., additional, Kielbasa, Szymon M., additional, Laros, Jeroen F.J., additional, and Veelken, Hendrik, additional

Published
2018
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213. Slit-Robo Pathway Is Clinically Relevant and May Represent a Potential Target in Acute Promyelocytic Leukemia

Author

Weinhäuser, Isabel, primary, Pereira-Martins, Diego Antonio, additional, Ortiz, Cesar, additional, Schiavinato, Josiane Lilian, additional, Bonaldo, Camila, additional, Koury, Luisa C, additional, De Deus Wagatsuma, Virginia Mara, additional, Melo, Raul Antônio Morais, additional, Bittencourt, Rosane, additional, Pagnano, Katia B, additional, Fagundes, Evandro Maranhão, additional, Gloria, Ana Beatriz F., additional, Kerbauy, Fabio R., additional, Chauffaille, Maria de Lourdes, additional, Pasquini, Ricardo, additional, Tallman, Martin S., additional, Ribeiro, Raul, additional, Dillon, Richard, additional, Keating, Armand, additional, Ganser, Arnold, additional, Lowenberg, Bob, additional, Valk, Peter, additional, Lo-Coco, Francesco, additional, Sanz, Miguel A., additional, Berliner, Nancy, additional, Lucena-Araujo, Antonio R., additional, and Rego, Eduardo Magalhães, additional

Published
2018
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215. Metformintreatment Overcomes ATRA-Resistance in Acute Promyelocytic Leukemia and Increases FOXO3A Expression

Author

Pereira-Martins, Diego Antonio, primary, Ortiz, Cesar, additional, Franca-Neto, Pedro Luis, additional, Weinhäuser, Isabel, additional, Schiavinato, Josiane Lilian, additional, Palma, Patrícia Vianna Bonini, additional, Bonaldo, Camila, additional, Koury, Luisa C A, additional, Do Nascimento, Mariane Cristina, additional, Melo, Raul Antônio Morais, additional, Bittencourt, Rosane, additional, Pagnano, Katia B B, additional, Pasquini, Ricardo, additional, Fagundes, Evandro Maranhão, additional, Gloria, Ana Beatriz F., additional, Kerbauy, Fabio R., additional, Chauffaille, Maria de Lourdes, additional, Keating, Armand, additional, Tallman, Martin S., additional, Ribeiro, Raul, additional, Dillon, Richard, additional, Ganser, Arnold, additional, Lowenberg, Bob, additional, Valk, Peter, additional, Lo-Coco, Francesco, additional, Sanz, Miguel A., additional, Berliner, Nancy, additional, Lucena-Araujo, Antonio R., additional, and Rego, Eduardo Magalhães, additional

Published
2018
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216. A Leukemic Progression Model of Severe Congenital Neutropenia Uncovers a Novel Mechanism of AML Development Involving Elevated Inflammatory Responses, Mutation of CXXC4 and Decreased TET2 Levels

Author

Olofsen, Patricia, primary, Fatrai, Szabolcs, additional, van Strien, Paulette, additional, Obenauer, Julia, additional, Hoogenboezem, Remco, additional, Erpelinck-Verschueren, Claudia, additional, Roovers, Onno, additional, Haferlach, Torsten, additional, Valk, Peter, additional, Schneider, Rebekka, additional, De Pater, Emma, additional, and Touw, Ivo, additional

Published
2018
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217. MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML

Author

Sanders, Mathijs A., primary, Chew, Edward, additional, Flensburg, Christoffer, additional, Zeilemaker, Annelieke, additional, Miller, Sarah E., additional, al Hinai, Adil S., additional, Bajel, Ashish, additional, Luiken, Bram, additional, Rijken, Melissa, additional, Mclennan, Tamara, additional, Hoogenboezem, Remco M., additional, Kavelaars, François G., additional, Fröhling, Stefan, additional, Blewitt, Marnie E., additional, Bindels, Eric M., additional, Alexander, Warren S., additional, Löwenberg, Bob, additional, Roberts, Andrew W., additional, Valk, Peter J. M., additional, and Majewski, Ian J., additional

Published
2018
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219. Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation.

Author

Kemps, Paul G, Hebeda, Konnie M, Pals, Steven T, Verdijk, Robert M, Lam, King H, Bruggink, Annette H, Lil, Heleen S, Ruiterkamp, Bart, Heer, Koen, Laar, Jan AM, Valk, Peter JM, Mutsaers, Pim, Levin, Mark‐David, Hogendoorn, Pancras CW, and Halteren, Astrid GS

Subjects
ACUTE myeloid leukemia, BONE marrow cells, BEARINGS (Machinery), CHRONIC leukemia, FOLLICULAR dendritic cells, RETICULUM cell sarcoma, SOMATIC mutation
Abstract

Histiocytic disorders are a spectrum of rare diseases characterised by the accumulation of macrophage‐, dendritic cell‐, or monocyte‐differentiated cells in various tissues and organs. The discovery of recurrent genetic alterations in many of these histiocytoses has led to their recognition as clonal neoplastic diseases. Moreover, the identification of the same somatic mutation in histiocytic lesions and peripheral blood and/or bone marrow cells from histiocytosis patients has provided evidence for systemic histiocytic neoplasms to originate from haematopoietic stem/progenitor cells (HSPCs). Here, we investigated associations between histiocytic disorders and additional haematological malignancies bearing the same genetic alteration(s) using the nationwide Dutch Pathology Registry. By searching on pathologist‐assigned diagnostic terms for the various histiocytic disorders, we identified 4602 patients with a putative histopathological diagnosis of a histiocytic disorder between 1971 and 2019. Histiocytosis‐affected tissue samples of 187 patients had been analysed for genetic alterations as part of routine molecular diagnostics, including from nine patients with an additional haematological malignancy. Among these patients, we discovered three cases with different histiocytic neoplasms and additional haematological malignancies bearing identical oncogenic mutations, including one patient with concomitant KRAS p.A59E mutated histiocytic sarcoma and chronic myelomonocytic leukaemia (CMML), one patient with synchronous NRAS p.G12V mutated indeterminate cell histiocytosis and CMML, and one patient with subsequent NRAS p.Q61R mutated Erdheim–Chester disease and acute myeloid leukaemia. These cases support the existence of a common haematopoietic cell‐of‐origin in at least a proportion of patients with a histiocytic neoplasm and additional haematological malignancy. In addition, they suggest that driver mutations in particular genes (e.g. N/KRAS) may specifically predispose to the development of an additional clonally related haematological malignancy or secondary histiocytic neoplasm. Finally, the putative existence of derailed multipotent HSPCs in these patients emphasises the importance of adequate (bone marrow) staging, molecular analysis and long‐term follow‐up of all histiocytosis patients. [ABSTRACT FROM AUTHOR]

Published
2021
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220. miR‐15a‐5p and miR‐21‐5p contribute to chemoresistance in cytogenetically normal acute myeloid leukaemia by targeting PDCD4, ARL2 and BTG2.

Author

Vandewalle, Virginie, Essaghir, Ahmed, Bollaert, Emeline, Lenglez, Sandrine, Graux, Carlos, Schoemans, Hélène, Saussoy, Pascale, Michaux, Lucienne, Valk, Peter J. M., Demoulin, Jean‐Baptiste, and Havelange, Violaine

Subjects
ACUTE myeloid leukemia, DRUG resistance in cancer cells, NON-coding RNA, NUCLEOTIDE sequence, CYTOGENETICS, MICRORNA
Abstract

Cytarabine and daunorubicin are old drugs commonly used in the treatment of acute myeloid leukaemia (AML). Refractory or relapsed disease because of chemotherapy resistance is a major issue. microRNAs (miRNAs) were incriminated in resistance. This study aimed to identify miRNAs involved in chemoresistance in AML patients and to define their target genes. We focused on cytogenetically normal AML patients with wild‐type NPM1 without FLT3‐ITD as the treatment of this subset of patients with intermediate‐risk cytogenetics is not well established. We analysed baseline AML samples by small RNA sequencing and compared the profile of chemoresistant to chemosensitive AML patients. Among the miRNAs significantly overexpressed in chemoresistant patients, we revealed miR‐15a‐5p and miR‐21‐5p as miRNAs with a major role in chemoresistance in AML. We showed that miR‐15a‐5p and miR‐21‐5p overexpression decreased apoptosis induced by cytarabine and/or daunorubicin. PDCD4, ARL2 and BTG2 genes were found to be targeted by miR‐15a‐5p, as well as PDCD4 and BTG2 by miR‐21‐5p. Inhibition experiments of the three target genes reproduced the functional effect of both miRNAs on chemosensitivity. Our study demonstrates that miR‐15a‐5p and miR‐21‐5p are overexpressed in a subgroup of chemoresistant AML patients. Both miRNAs induce chemoresistance by targeting three pro‐apoptotic genes PDCD4, ARL2 and BTG2. [ABSTRACT FROM AUTHOR]

Published
2021
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221. SNPExpress: integrated visualization of genome-wide genotypes, copy numbers and gene expression levels

Author

Horsman Sebastiaan, Abbas Saman, Geertsma-Kleinekoort Wendy MC, Verhaak Roel GW, Sanders Mathijs A, van der Spek Peter J, Löwenberg Bob, and Valk Peter JM

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Accurate analyses of comprehensive genome-wide SNP genotyping and gene expression data sets is challenging for many researchers. In fact, obtaining an integrated view of both large scale SNP genotyping and gene expression is currently complicated since only a limited number of appropriate software tools are available. Results We present SNPExpress, a software tool to accurately analyze Affymetrix and Illumina SNP genotype calls, copy numbers, polymorphic copy number variations (CNVs) and Affymetrix gene expression in a combinatorial and efficient way. In addition, SNPExpress allows concurrent interpretation of these items with Hidden-Markov Model (HMM) inferred Loss-of-Heterozygosity (LOH)- and copy number regions. Conclusion The combined analyses with the easily accessible software tool SNPExpress will not only facilitate the recognition of recurrent genetic lesions, but also the identification of critical pathogenic genes.

Published
2008
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223. HeatMapper: powerful combined visualization of gene expression profile correlations, genotypes, phenotypes and sample characteristics

Author

Moorhouse Michael J, Horsman Sebastiaan, Delwel Ruud, Bijl Maarten A, Sanders Mathijs A, Verhaak Roel GW, van der Spek Peter J, Löwenberg Bob, and Valk Peter JM

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Accurate interpretation of data obtained by unsupervised analysis of large scale expression profiling studies is currently frequently performed by visually combining sample-gene heatmaps and sample characteristics. This method is not optimal for comparing individual samples or groups of samples. Here, we describe an approach to visually integrate the results of unsupervised and supervised cluster analysis using a correlation plot and additional sample metadata. Results We have developed a tool called the HeatMapper that provides such visualizations in a dynamic and flexible manner and is available from http://www.erasmusmc.nl/hematologie/heatmapper/. Conclusion The HeatMapper allows an accessible and comprehensive visualization of the results of gene expression profiling and cluster analysis.

Published
2006
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224. The effect of oligonucleotide microarray data pre-processing on the analysis of patient-cohort studies

Author

Reinders Marcel JT, Valk Peter JM, Lowenberg Bob, Staal Frank JT, Verhaak Roel GW, and de Ridder Dick

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Intensity values measured by Affymetrix microarrays have to be both normalized, to be able to compare different microarrays by removing non-biological variation, and summarized, generating the final probe set expression values. Various pre-processing techniques, such as dChip, GCRMA, RMA and MAS have been developed for this purpose. This study assesses the effect of applying different pre-processing methods on the results of analyses of large Affymetrix datasets. By focusing on practical applications of microarray-based research, this study provides insight into the relevance of pre-processing procedures to biology-oriented researchers. Results Using two publicly available datasets, i.e., gene-expression data of 285 patients with Acute Myeloid Leukemia (AML, Affymetrix HG-U133A GeneChip) and 42 samples of tumor tissue of the embryonal central nervous system (CNS, Affymetrix HuGeneFL GeneChip), we tested the effect of the four pre-processing strategies mentioned above, on (1) expression level measurements, (2) detection of differential expression, (3) cluster analysis and (4) classification of samples. In most cases, the effect of pre-processing is relatively small compared to other choices made in an analysis for the AML dataset, but has a more profound effect on the outcome of the CNS dataset. Analyses on individual probe sets, such as testing for differential expression, are affected most; supervised, multivariate analyses such as classification are far less sensitive to pre-processing. Conclusion Using two experimental datasets, we show that the choice of pre-processing method is of relatively minor influence on the final analysis outcome of large microarray studies whereas it can have important effects on the results of a smaller study. The data source (platform, tissue homogeneity, RNA quality) is potentially of bigger importance than the choice of pre-processing method.

Published
2006
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225. Splicing factor gene mutations in acute myeloid leukemia offer additive value if incorporated in current risk classification

Author

van der Werf, Inge, Wojtuszkiewicz, Anna, Meggendorfer, Manja, Hutter, Stephan, Baer, Constance, Heymans, Martijn, Valk, Peter J. M., Kern, Wolfgang, Haferlach, Claudia, Janssen, Jeroen J. W. M., Ossenkoppele, Gert J., Cloos, Jacqueline, and Haferlach, Torsten

Abstract

Splicing factor (SF) mutations are important contributors to the pathogenesis of hematological malignancies; however, their relevance in risk classification of acute myeloid leukemia (AML) warrants further investigation. To gain more insight into the characteristics of patients with AML carrying SF mutations, we studied their association with clinical features, cytogenetic and molecular abnormalities, and clinical outcome in a large cohort of 1447 patients with AML and high-risk myelodysplastic syndrome. SF mutations were identified in 22% of patients and were associated with multiple unfavorable clinical features, such as older age, antecedent myeloid disorders, and adverse risk factors (mutations in RUNX1 and ASXL1). Furthermore, they had significantly shorter event-free and overall survival. Notably, in European LeukemiaNet (ELN) 2017 favorable- and intermediate-risk groups, SF3B1 mutations were indicative of relatively poor prognosis. In addition, patients carrying concomitant SF mutations and RUNX1 mutations had a particularly adverse prognosis. In patients without any of the 4 most common SF mutations, RUNX1 mutations were associated with relatively good outcome, which was comparable to that of intermediate-risk patients. In this study, we propose that SF mutations be considered for incorporation into prognostic classification systems. First, SF3B1 mutations could be considered an intermediate prognostic factor when co-occurring with favorable risk features and as an adverse prognostic factor for patients currently categorized as having intermediate risk, according to the ELN 2017 classification. Second, the prognostic value of the current adverse factor RUNX1 mutations seems to be limited to its co-occurrence with SF mutations.

Published
2021
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227. Genomic and evolutionary portraits of disease relapse in acute myeloid leukemia

Author

Rapaport, Franck, Neelamraju, Yaseswini, Baslan, Timour, Hassane, Duane, Gruszczynska, Agata, Robert de Massy, Marc, Farnoud, Noushin, Haddox, Samuel, Lee, Tak, Medina-Martinez, Juan, Sheridan, Caroline, Thurmond, Alexis, Becker, Michael, Bekiranov, Stefan, Carroll, Martin, Moses Murdock, Heardly, Valk, Peter J. M., Bullinger, Lars, D’Andrea, Richard, Lowe, Scott W., Neuberg, Donna, Levine, Ross L., Melnick, Ari, and Garrett-Bakelman, Francine E.

Published
2021
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228. 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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234. Abstract 1366:MBD4guards against DNA damage from methylcytosine deamination

Author

Chew, Edward, primary, Sanders, Mathijs A., additional, Flensburg, Christoffer, additional, Zeilemaker, Annelieke, additional, Miller, Sarah E., additional, Hinai, Adil S. al, additional, Bajel, Ashish, additional, Luiken, Bram, additional, Rijken, Melissa, additional, Mclennan, Tamara, additional, Hoogenboezem, Remco M., additional, Kavelaars, François G., additional, Blewitt, Marnie E., additional, Bindels, Eric M., additional, Alexander, Warren S., additional, Löwenberg, Bob, additional, Roberts, Andrew W., additional, Majewski, Ian J., additional, and Valk, Peter J., additional

Published
2018
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235. Correction: Publisher Correction: miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia

Author

Li, Zejuan, primary, Huang, Hao, additional, Chen, Ping, additional, He, Miao, additional, Li, Yuanyuan, additional, Arnovitz, Stephen, additional, Jiang, Xi, additional, He, Chunjiang, additional, Hyjek, Elizabeth, additional, Zhang, Jun, additional, Zhang, Zhiyu, additional, Elkahloun, Abdel, additional, Cao, Donglin, additional, Shen, Chen, additional, Wunderlich, Mark, additional, Wang, Yungui, additional, Neilly, Mary Beth, additional, Jin, Jie, additional, Wei, Minjie, additional, Lu, Jun, additional, Valk, Peter J. M., additional, Delwel, Ruud, additional, Lowenberg, Bob, additional, Le Beau, Michelle M., additional, Vardiman, James, additional, Mulloy, James C., additional, Zeleznik-Le, Nancy J., additional, Liu, Paul P., additional, Zhang, Jiwang, additional, and Chen, Jianjun, additional

Published
2018
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236. Molecular Minimal Residual Disease in Acute Myeloid Leukemia

Author

Jongen-Lavrencic, Mojca, primary, Grob, Tim, additional, Hanekamp, Diana, additional, Kavelaars, François G., additional, al Hinai, Adil, additional, Zeilemaker, Annelieke, additional, Erpelinck-Verschueren, Claudia A.J., additional, Gradowska, Patrycja L., additional, Meijer, Rosa, additional, Cloos, Jacqueline, additional, Biemond, Bart J., additional, Graux, Carlos, additional, van Marwijk Kooy, Marinus, additional, Manz, Markus G., additional, Pabst, Thomas, additional, Passweg, Jakob R., additional, Havelange, Violaine, additional, Ossenkoppele, Gert J., additional, Sanders, Mathijs A., additional, Schuurhuis, Gerrit J., additional, Löwenberg, Bob, additional, and Valk, Peter J.M., additional

Published
2018
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239. The application of an integrated clinical, cytogenetic, and molecular risk stratification for acute myeloid leukemia patients using a central laboratory in a Brazilian multicentric study

Author

Borges da Silva, Fernanda, primary, de Figueiredo-Pontes, Lorena Lobo, additional, Madeira, Maria Isabel Ayrosa, additional, Corrêa de Araujo Koury, Luisa, additional, Gouvêa de Lima, Ana Silvia, additional, Santos Scheucher, Priscila, additional, Coelho-Silva, Juan Luiz, additional, Pagnano, Katia Borgia Barbosa, additional, Pallota, Ronald, additional, de Lourdes Chauffaille, Maria, additional, Oltramari, Marcos Roberto Pedron, additional, Bittencourt, Rosane Isabel, additional, Higashi, Marcia, additional, Bendlin, Rodrigo Miguel, additional, Rodrigues Pereira Velloso, Elvira Deolinda, additional, Lowenberg, Bob, additional, Ganser, Arnold, additional, Berliner, Nancy, additional, Valk, Peter, additional, Magalhães Rego, Eduardo, additional, and Traina, Fabiola, additional

Published
2017
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240. Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML

Author

Jongen-Lavrencic, Mojca, primary, Grob, Tim, additional, Kavelaars, Francois G., additional, Al Hinai, Adil S.A., additional, Zeilemaker, Annelieke, additional, Erpelinck-Verschueren, Claudia A.J., additional, Norden, Yvette, additional, Meijer, Rosa, additional, Biemond, Bart J., additional, Graux, Carlos, additional, van Marwijk Kooij, Marinus, additional, Manz, Markus G., additional, Pabst, Thomas, additional, Havelange, Violaine, additional, Passweg, Jakob R., additional, Ossenkoppele, Gert J., additional, Schuurhuis, Gerrit Jan, additional, Sanders, Mathijs A., additional, Löwenberg, Bob, additional, and Valk, Peter J.M., additional

Published
2017
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241. Germline loss of MBD4 predisposes to leukaemia due to a mutagenic cascade driven by 5mC

Author

Sanders, Mathijs A., primary, Chew, Edward, additional, Flensburg, Christoffer, additional, Zeilemaker, Annelieke, additional, Miller, Sarah E., additional, al Hinai, Adil S., additional, Bajel, Ashish, additional, Luiken, Bram, additional, Rijken, Melissa, additional, Mclennan, Tamara, additional, Hoogenboezem, Remco M., additional, Kavelaars, François G., additional, Blewitt, Marnie E., additional, Bindels, Eric M., additional, Alexander, Warren S., additional, Löwenberg, Bob, additional, Roberts, Andrew W., additional, Valk, Peter J.M., additional, and Majewski, Ian J., additional

Published
2017
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246. Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial

Author

Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, Gradowska, Patrycja, Biemond, Bart J., Spertini, Olivier, Vellenga, Edo, Griskevicius, Laimonas, Tick, Lidwine W., Jongen-Lavrencic, Mojca, van Marwijk Kooy, Marinus, Vekemans, Marie-Christiane, van der Velden, Walter J.F.M., Beverloo, Berna, Michaux, Lucienne, Graux, Carlos, Deeren, Dries, de Weerdt, Okke, van Esser, Joost W.J., Bargetzi, Mario, Klein, Saskia K., Gadisseur, Alain, Westerweel, Peter E., Veelken, Hendrik, Gregor, Michael, Silzle, Tobias, van Lammeren-Venema, Daniëlle, Moors, Ine, Breems, Dimitri A., Hoogendoorn, Mels, Legdeur, Marie-Cecile J.C., Fischer, Thomas, Kuball, Juergen, Cornelissen, Jan, Porkka, Kimmo, Juliusson, Gunnar, Meyer, Peter, Höglund, Martin, Gjertsen, Bjorn T., Janssen, Jeroen J.W.M., Huls, Gerwin, Passweg, Jakob, Cloos, Jacqueline, Valk, Peter J.M., van Elssen, Catharina H.M.J., Manz, Markus G., Floisand, Yngvar, and Ossenkoppele, Gert J.

Abstract

Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)–adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% ± 2% standard error and overall survival, 54% ± 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study.

Published
2021
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247. Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing

Author

Arindrarto, Wibowo, Borràs, Daniel M., de Groen, Ruben A. L., van den Berg, Redmar R., Locher, Irene J., van Diessen, Saskia A. M. E., van der Holst, Rosalie, van der Meijden, Edith D., Honders, M. Willy, de Leeuw, Rick H., Verlaat, Wina, Jedema, Inge, Kroes, Wilma G. M., Knijnenburg, Jeroen, van Wezel, Tom, Vermaat, Joost S. P., Valk, Peter J. M., Janssen, Bart, de Knijff, Peter, van Bergen, Cornelis A. M., van den Akker, Erik B., Hoen, Peter A. C. ’t, Kielbasa, Szymon M., Laros, Jeroen F. J., Griffioen, Marieke, and Veelken, Hendrik

Abstract

Acute myeloid leukemia (AML) is caused by genetic aberrations that also govern the prognosis of patients and guide risk-adapted and targeted therapy. Genetic aberrations in AML are structurally diverse and currently detected by different diagnostic assays. This study sought to establish whole transcriptome RNA sequencing as single, comprehensive, and flexible platform for AML diagnostics. We developed HAMLET (Human AML Expedited Transcriptomics) as bioinformatics pipeline for simultaneous detection of fusion genes, small variants, tandem duplications, and gene expression with all information assembled in an annotated, user-friendly output file. Whole transcriptome RNA sequencing was performed on 100 AML cases and HAMLET results were validated by reference assays and targeted resequencing. The data showed that HAMLET accurately detected all fusion genes and overexpression of EVI1irrespective of 3q26 aberrations. In addition, small variants in 13 genes that are often mutated in AML were called with 99.2% sensitivity and 100% specificity, and tandem duplications in FLT3and KMT2Awere detected by a novel algorithm based on soft-clipped reads with 100% sensitivity and 97.1% specificity. In conclusion, HAMLET has the potential to provide accurate comprehensive diagnostic information relevant for AML classification, risk assessment and targeted therapy on a single technology platform.

Published
2021
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248. Secondary CNL after SAA reveals insights in leukemic transformation of bone marrow failure syndromes

Author

Schmied, Laurent, Olofsen, Patricia A., Lundberg, Pontus, Tzankov, Alexandar, Kleber, Martina, Halter, Jörg, Uhr, Mario, Valk, Peter J. M., Touw, Ivo P., Passweg, Jakob, and Drexler, Beatrice

Abstract

Acquired aplastic anemia and severe congenital neutropenia (SCN) are bone marrow (BM) failure syndromes of different origin, however, they share a common risk for secondary leukemic transformation. Here, we present a patient with severe aplastic anemia (SAA) evolving to secondary chronic neutrophilic leukemia (CNL; SAA-CNL). We show that SAA-CNL shares multiple somatic driver mutations in CSF3R, RUNX1, and EZH2/SUZ12 with cases of SCN that transformed to myelodysplastic syndrome or acute myeloid leukemia (AML). This molecular connection between SAA-CNL and SCN progressing to AML (SCN-AML) prompted us to perform a comparative transcriptome analysis on nonleukemic CD34high hematopoietic stem and progenitor cells, which showed transcriptional profiles that resemble indicative of interferon-driven proinflammatory responses. These findings provide further insights in the mechanisms underlying leukemic transformation in BM failure syndromes.

Published
2020
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249. TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML

Author

Vadakekolathu, Jayakumar, Lai, Catherine, Reeder, Stephen, Church, Sarah E., Hood, Tressa, Lourdusamy, Anbarasu, Rettig, Michael P., Aldoss, Ibrahim, Advani, Anjali S., Godwin, John, Wieduwilt, Matthew J., Arellano, Martha, Muth, John, Yau, Tung On, Ravandi, Farhad, Sweet, Kendra, Altmann, Heidi, Foulds, Gemma A., Stölzel, Friedrich, Middeke, Jan Moritz, Ciciarello, Marilena, Curti, Antonio, Valk, Peter J. M., Löwenberg, Bob, Gojo, Ivana, Bornhäuser, Martin, DiPersio, John F., Davidson-Moncada, Jan K., and Rutella, Sergio

Abstract

Somatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37% to 46% of acute myeloid leukemia (AML) with adverse-risk cytogenetics and correlate with primary induction failure, high risk of relapse, and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53-mutated AML and determine whether TP53 abnormalities identify a patient subgroup that may benefit from immunotherapy with flotetuzumab, an investigational CD123 × CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples from patients with TP53-mutated (n = 42) and TP53-wild-type (TP53-WT) AML (n = 22) and 45 BM samples from patients who received flotetuzumab for relapsed/refractory (R/R) AML (15 cases with TP53 mutations and/or 17p deletion). The comparison between TP53-mutated and TP53-WT primary BM samples showed higher expression of IFNG, FOXP3, immune checkpoints, markers of immune senescence, and phosphatidylinositol 3-kinase-Akt and NF-κB signaling intermediates in the former cohort and allowed the discovery of a 34-gene immune classifier prognostic for survival in independent validation series. Finally, 7 out of 15 patients (47%) with R/R AML and TP53 abnormalities showed complete responses to flotetuzumab (<5% BM blasts) on the CP-MGD006-01 clinical trial (NCT #02152956) and had significantly higher tumor inflammation signature, FOXP3, CD8, inflammatory chemokine, and PD1 gene expression scores at baseline compared with nonresponders. Patients with TP53 abnormalities who achieved a complete response experienced prolonged survival (median, 10.3 months; range, 3.3-21.3 months). These results encourage further study of flotetuzumab immunotherapy in patients with TP53-mutated AML.

Published
2020
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250. TP53abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML

Author

Vadakekolathu, Jayakumar, Lai, Catherine, Reeder, Stephen, Church, Sarah E., Hood, Tressa, Lourdusamy, Anbarasu, Rettig, Michael P., Aldoss, Ibrahim, Advani, Anjali S., Godwin, John, Wieduwilt, Matthew J., Arellano, Martha, Muth, John, Yau, Tung On, Ravandi, Farhad, Sweet, Kendra, Altmann, Heidi, Foulds, Gemma A., Stölzel, Friedrich, Middeke, Jan Moritz, Ciciarello, Marilena, Curti, Antonio, Valk, Peter J.M., Löwenberg, Bob, Gojo, Ivana, Bornhäuser, Martin, DiPersio, John F., Davidson-Moncada, Jan K., and Rutella, Sergio

Abstract

Somatic TP53mutations and 17p deletions with genomic loss of TP53occur in 37% to 46% of acute myeloid leukemia (AML) with adverse-risk cytogenetics and correlate with primary induction failure, high risk of relapse, and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53-mutated AML and determine whether TP53abnormalities identify a patient subgroup that may benefit from immunotherapy with flotetuzumab, an investigational CD123 × CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples from patients with TP53-mutated (n = 42) and TP53-wild-type (TP53-WT) AML (n = 22) and 45 BM samples from patients who received flotetuzumab for relapsed/refractory (R/R) AML (15 cases with TP53mutations and/or 17p deletion). The comparison between TP53-mutated and TP53-WT primary BM samples showed higher expression of IFNG, FOXP3, immune checkpoints, markers of immune senescence, and phosphatidylinositol 3-kinase-Akt and NF-κB signaling intermediates in the former cohort and allowed the discovery of a 34-gene immune classifier prognostic for survival in independent validation series. Finally, 7 out of 15 patients (47%) with R/R AML and TP53abnormalities showed complete responses to flotetuzumab (<5% BM blasts) on the CP-MGD006-01 clinical trial (NCT #02152956) and had significantly higher tumor inflammation signature, FOXP3, CD8, inflammatory chemokine, and PD1gene expression scores at baseline compared with nonresponders. Patients with TP53abnormalities who achieved a complete response experienced prolonged survival (median, 10.3 months; range, 3.3-21.3 months). These results encourage further study of flotetuzumab immunotherapy in patients with TP53-mutated AML.

Published
2020
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