Mark Verheul

Oncode Institute

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Ruben van Boxtel

Princess Máxima Center

Markus J. van Roosmalen

Princess Máxima Center

Arianne M. Brandsma

Princess Máxima Center

Rurika Oka

Princess Máxima Center

Edwin Cuppen

Hartwig Medical Foundation

Eline J.M. Bertrums

Princess Máxima Center

Freek Manders

Oncode Institute

Gilbert Monod de Froideville

Mirjam E. Belderbos

Princess Máxima Center

Joske Ubels

Princess Máxima Center

Cooperative Institutions

University Medical Center Utrecht

Utrecht University

Oncode Institute

Princess Máxima Center

Hubrecht Institute for Developmental Biology and Stem Cell Research

Radboud University Nijmegen

Radboud University Medical Center

Royal Netherlands Academy of Arts and Sciences

Cancer Genomics Centre

Heidelberg University

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Retrospective Lineage Tracing of Pediatric Acute Myeloid Leukemia Using Single-Cell Whole Genome Sequencing

Blood (2022)

Eline J.M. Bertrums Sjors Middelkamp Inge M. van der Werf Freek Manders Arianne M. Brandsma

RUNX1

CEBPA

10.1182/blood-2022-166051

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Frontmatter

Amsterdam University Press eBooks (2021)

Gilbert Monod De Froideville Mark Verheul Elmer Dumlao

10.1515/9789048554850-fm

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Supplementary Figure from Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms

Eline J.M. Bertrums Axel Rosendahl Huber Jurrian K. de Kanter Arianne M. Brandsma Anaïs J.C.N. van Leeuwen

Supplementary Figure from Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms

Blood cancer

Cancer Therapy

10.1158/2159-8290.22541080.v1

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A genome-wide SNP panel for mapping and association studies in the rat

BMC Genomics (2008)

Isaäc J. Nijman Sylvia Kuipers Mark Verheul Victor Guryev Edwin Cuppen

The laboratory rat (Rattus norvegicus) is an important model for human disease, and is extensively used for studying complex traits for example in the physiological and pharmacological fields. To facilitate genetic studies like QTL mapping, genetic makers that can be easily typed, like SNPs, are essential.A genome-wide set of 820 SNP assays was designed for the KASPar genotyping platform, which uses a technique based on allele specific oligo extension and energy transfer-based detection. SNPs were chosen to be equally spread along all chromosomes except Y and to be polymorphic between Brown Norway and SS or Wistar rat strains based on data from the rat HapMap EU project. This panel was tested on 38 rats of 34 different strains and 3 wild rats to determine the level of polymorphism and to generate a phylogenetic network to show their genetic relationships. As a proof of principle we used this panel to map an obesity trait in Zucker rats and confirmed significant linkage (LOD 122) to chromosome 5: 119-129 Mb, where the leptin receptor gene (Lepr) is located (chr5: 122 Mb).We provide a fast and cost-effective platform for genome-wide SNP typing, which can be used for first-pass genetic mapping and association studies in a wide variety of rat strains.

SNP

Genome-wide Association Study

Genetic Association

10.1186/1471-2164-9-95

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Systematic generation of in vivo G protein-coupled receptor mutants in the rat

The Pharmacogenomics Journal (2010)

Ruben van Boxtel Bas Vroling Pim W. Toonen Isaäc J. Nijman H van Roekel

G-protein-coupled receptors (GPCRs) constitute a large family of cell surface receptors that are involved in a wide range of physiological and pathological processes, and are targets for many therapeutic interventions. However, genetic models in the rat, one of the most widely used model organisms in physiological and pharmacological research, are largely lacking. Here, we applied N-ethyl-N-nitrosourea (ENU)-driven target-selected mutagenesis to generate an in vivo GPCR mutant collection in the rat. A pre-selected panel of 250 human GPCR homologs was screened for mutations in 813 rats, resulting in the identification of 131 non-synonymous mutations. From these, seven novel potential rat gene knockouts were established as well as 45 lines carrying missense mutations in various genes associated with or involved in human diseases. We provide extensive in silico modeling results of the missense mutations and show experimental data, suggesting loss-of-function phenotypes for several models, including Mc4r and Lpar1. Taken together, the approach used resulted not only in a set of novel gene knockouts, but also in allelic series of more subtle amino acid variants, similar as commonly observed in human disease. The mutants presented here may greatly benefit studies to understand specific GPCR function and support the development of novel therapeutic strategies.

Gene knockout

Gene targeting

Knockout mouse

Loss function

10.1038/tpj.2010.44

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Somatic Mutations Reveal Lineage Relationships and Age-Related Mutagenesis in Human Hematopoiesis

Cell Reports (2018)

Fernando G. Osorio Axel Rosendahl Huber Rurika Oka Mark Verheul Sachin Patel

Mutation accumulation during life can contribute to hematopoietic dysfunction; however, the underlying dynamics are unknown. Somatic mutations in blood progenitors can provide insight into the rate and processes underlying this accumulation, as well as the developmental lineage tree and stem cell division numbers. Here, we catalog mutations in the genomes of human-bone-marrow-derived and umbilical-cord-blood-derived hematopoietic stem and progenitor cells (HSPCs). We find that mutations accumulate gradually during life with approximately 14 base substitutions per year. The majority of mutations were acquired after birth and could be explained by the constant activity of various endogenous mutagenic processes, which also explains the mutation load in acute myeloid leukemia (AML). Using these mutations, we construct a developmental lineage tree of human hematopoiesis, revealing a polyclonal architecture and providing evidence that developmental clones exhibit multipotency. Our approach highlights features of human native hematopoiesis and its implications for leukemogenesis.

Lineage (genetic)

Hematopoietic stem cell

10.1016/j.celrep.2018.11.014

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Data from Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms

Eline J.M. Bertrums Axel Rosendahl Huber Jurrian K. de Kanter Arianne M. Brandsma Anaïs J.C.N. van Leeuwen

<div>Abstract<p>Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes to the mutation burden and clonal composition of healthy tissues early in life. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPC) before and after cancer treatment of 24 children. Of these children, 19 developed therapy-related myeloid neoplasms (t-MN). Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naïve cells accumulate during 16 years of life, with excesses up to 80 years. In most children, these additional mutations were induced by clock-like processes, which are also active during healthy aging. Other patients harbored mutations that could be directly attributed to treatments like platinum-based drugs and thiopurines. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure.</p>Significance:<p>Our study shows that chemotherapy increases the mutation burden of normal blood cells in cancer survivors. Only few drugs damage the DNA directly, whereas in most patients, chemotherapy-induced mutations are caused by processes similar to those present during normal aging.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-8-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 1825</a></i></p></div>

10.1158/2159-8290.c.6549550.v1

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Generation of gene knockouts and mutant models in the laboratory rat by ENU-driven target-selected mutagenesis

Pharmacogenetics and Genomics (2006)

Bart M. G. Smits Josine Mudde José van de Belt Mark Verheul Berend Olivier

The rat is one of the most important model organisms for biomedical and pharmacological research. However, the generation of novel models for studying specific aspects of human diseases largely depends on selection for specific traits using existing rat strains, thereby solely depending on naturally occurring variation. This study aims to provide the tools to manipulate the rat genome in a more directed way.We developed robust, automated, and scaleable reverse genetic methodology based on ENU (N-ethyl-N-nitrosourea)-driven target-selected mutagenesis. Optimal mutagenesis conditions have been determined in three different rat strains and a universal, rapid, and cost-effective dideoxy resequencing-based screening setup was established for mutation discovery. The effectiveness of the approach is illustrated by the identification of 120 induced mutations in a set of genes of interest, including six that result in unique rat knockout models due to the introduction of premature stop codons. In addition, 56 mutations were found that change amino acids, including critical residues in transmembrane domains of receptors and channels.The approach described here allows for the systematic generation of knockout and protein function altering alleles in the rat. The resulting induced rat models will be powerful tools for studying many aspects of a wide variety of human diseases.

Gene knockout

Gene targeting

10.1097/01.fpc.0000184960.82903.8f

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Citations (196)

SMN1 gene duplications are associated with sporadic ALS

Neurology (2012)

Hylke M. Blauw C. Barnes Paul W.J. van Vught Wouter van Rheenen Mark Verheul

Objective:

To investigate the role of SMN1 and SMN2 copy number variation and point mutations in amyotrophic lateral sclerosis (ALS) pathogenesis in a large population.

Methods:

We conducted a genetic association study including 847 patients with ALS and 984 controls. We used multiplexed ligation-dependent probe amplification (MLPA) assays to determine SMN1 and SMN2 copy numbers and examined effects on disease susceptibility and disease course. Furthermore, we sequenced SMN genes to determine if SMN mutations were more prevalent in patients with ALS. A meta-analysis was performed with results from previous studies.

Results:

SMN1 duplications were associated with ALS susceptibility (odds ratio [OR] 2.07, 95% confidence interval [CI] 1.34–3.20, p = 0.001). A meta-analysis with previous data including 3,469 individuals showed a similar effect: OR 1.85, 95% CI 1.18–2.90, p = 0.008). SMN1 deletions and SMN2 copy number status were not associated with ALS. SMN1 or SMN2 copy number variants had no effect on survival or the age at onset of the disease. We found no enrichment of SMN point mutations in patients with ALS.

Conclusions:

Our data provide firm evidence for a role of common SMN1 duplications in ALS, and raise new questions regarding the disease mechanisms involved.

SMN1

10.1212/wnl.0b013e318249f697

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Data from Mutation Signatures of Pediatric Acute Myeloid Leukemia and Normal Blood Progenitors Associated with Differential Patient Outcomes

Arianne M. Brandsma Eline J.M. Bertrums Markus J. van Roosmalen Damon A. Hofman Rurika Oka

<div>Abstract<p>Acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis. However, the incidence of leukemia in children is higher than in young adults. Here we compare somatic mutations across pediatric acute myeloid leukemia (pAML) patient-matched leukemic blasts and hematopoietic stem and progenitor cells (HSPC), as well as HSPCs from age-matched healthy donors. HSPCs in the leukemic bone marrow have limited genetic relatedness and share few somatic mutations with the cell of origin of the malignant blasts, suggesting polyclonal hematopoiesis in patients with pAML. Compared with normal HSPCs, a subset of pAML cases harbored more somatic mutations and a distinct composition of mutational process signatures. We hypothesize that these cases might have arisen from a more committed progenitor. This subset had better outcomes than pAML cases with mutation burden comparable with age-matched healthy HSPCs. Our study provides insights into the etiology and patient stratification of pAML.</p>Significance:<p>Genome-wide analysis of pAML and patient-matched HSPCs provides new insights into the etiology of the disease and shows the clinical potential of these analyses for patient stratification.</p><p><i>This article is highlighted in the In This Issue feature, p. 403</i></p></div>

10.1158/2643-3230.c.6550159.v1

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