Publications by authors named "Gudrun Göhring"

155 Publications

BCR-ABL1 positive AML or CML in blast crisis? A pediatric case report with inv(3) and t(9;22) in the initial clone.

Cancer Genet 2021 Feb 19;254-255:70-74. Epub 2021 Feb 19.

Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany. Electronic address:

The co-occurrence of an inversion inv(3)(q21q26)/GATA2-MECOM and a Philadelphia translocation t(9;22)(q34;q11)/BCR-ABL1 in the context of chronic myeloid leukemia (CML) in blast crisis or acute myeloid leukemia (AML) has only rarely been described. To our knowledge, this co-occurrence has been reported in six pediatric patients with CML but not in pediatric patients with AML. Here, we report on a 7-year-old girl, who, presented with a t(9;22) and inv(3) in 14 of 15 metaphases and an additional monosomy 7 was detected in 5 of these metaphases (ISCN: 46,​XX,​inv(3)(q21q26),​t(9;22)(q34q11)[9]/45,​idem,​-7[5]/46,​XX[1]). The p190 BCR-ABL1 fusion transcript was detected by multiplex PCR and targeted RNA sequencing. Due to these results, a clear distinction between a CML in blast crisis and a BCR-ABL1 positive AML was not possible. The patient was treated according to the treatment recommendations of the AML-BFM study group and additionally received tyrosine kinase inhibitor therapy (Dasatinib). The treatment with Dasatinib was successful in eliminating the inv(3)/t(9;22) clone, but the ancestral inv(3) clone persisted. Based upon these findings we diagnosed an AML with inv(3) and a secondary acquisition of t(9;22). This treatment as well as an allogenic transplantation has led to a complete remission of the disease up to this date (21 months post diagnosis).
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http://dx.doi.org/10.1016/j.cancergen.2021.02.007DOI Listing
February 2021

Establishment of MHHi001-A-5, a GCaMP6f and RedStar dual reporter human iPSC line for in vitro and in vivo characterization and in situ tracing of iPSC derivatives.

Stem Cell Res 2021 Jan 30;52:102206. Epub 2021 Jan 30.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), REBIRTH Research Center for Translational Regenerative Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

Transgenic hiPSC lines carrying reporter genes represent valuable tools for functional characterization of iPSC derivatives, disease modelling and clinical evaluation of cell therapies. Here, the hiPSC line 'Phoenix' (Haase et al., 2017) was genetically engineered using TALEN-based integration of the calcium sensor GCaMP6f and RedStar reporter into the AAVS1 site. Characterization of undifferentiated cells and functional investigation of hiPSC-derived cardiomyocytes-containing BCTs showed a strong intracellular calcium transient-dependent GCaMP6f and eminent RedStar signal. Therefore, our dual reporter line provides an excellent tool to facilitate monitoring of engraftment, calcium fluctuations and coupling of iPSC derivatives such as cardiomyocytes in vitro and in vivo in animal models.
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http://dx.doi.org/10.1016/j.scr.2021.102206DOI Listing
January 2021

Unbalanced translocation der(5;17) resulting in a TP53 loss as recurrent aberration in myelodysplastic syndrome and acute myeloid leukemia with complex karyotype.

Genes Chromosomes Cancer 2021 Jan 24. Epub 2021 Jan 24.

Department of Human Genetics, Hannover Medical School, Hannover, Germany.

A complex karyotype, detected in myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), is associated with a reduced median survival. The most frequent chromosomal aberrations in complex karyotypes are deletions of 5q and 17p harboring the tumor suppressor gene TP53. The unbalanced translocation der(5;17) involving chromosome 5q and 17p is a recurrent aberration in MDS/AML, resulting in TP53 loss. We analyzed the karyotypes of 178 patients with an unbalanced translocation der(5;17) using fluorescence R-/G-banding analysis. Whenever possible, fluorescence in situ hybridization (FISH) (n = 138/141), multicolor FISH (n = 8), telomere length measurement (n = 9), targeted DNA sequencing (n = 13), array-CGH (n = 7) and targeted RNA sequencing (n = 2) were conducted. The der(5;17) aberration was accompanied with loss of genetic material in 7q (53%), -7 (27%), gain of 21q (29%), +8 (17%) and - 18 (16%) and all analyzed patients (n = 13) showed a (likely) pathogenic variant inTP53. The der(5;17) cohort showed significantly shortened telomeres in comparison to the healthy age-matched controls (P < .05), but there was no significant telomere shortening in comparison to MDS/AML patients with a complex karyotype without der(5;17). No fusion genes resulted from the unbalanced translocation. This study demonstrates that the unbalanced translocation der(5;17) is associated with a biallelic inactivation of TP53 due to a deletion of TP53 in one allele and a pathogenic variant of the second TP53 allele. Since the breakpoints are located within (near-) heterochromatic regions, alterations of DNA methylation or histone modifications may be involved in the generation of der(5;17).
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http://dx.doi.org/10.1002/gcc.22938DOI Listing
January 2021

Knockout of the HMG domain of the porcine SRY gene causes sex reversal in gene-edited pigs.

Proc Natl Acad Sci U S A 2021 Jan;118(2)

Institute of Farm Animal Genetics, Friedrich-Loeffler-Institut, Mariensee, 31535 Neustadt am Rübenberge, Germany;

The sex-determining region on the Y chromosome (SRY) is thought to be the central genetic element of male sex development in mammals. Pathogenic modifications within the SRY gene are associated with a male-to-female sex reversal syndrome in humans and other mammalian species, including rabbits and mice. However, the underlying mechanisms are largely unknown. To understand the biological function of the SRY gene, a site-directed mutational analysis is required to investigate associated phenotypic changes at the molecular, cellular, and morphological level. Here, we successfully generated a knockout of the porcine SRY gene by microinjection of two CRISPR-Cas ribonucleoproteins, targeting the centrally located "high mobility group" (HMG), followed by a frameshift mutation of the downstream SRY sequence. This resulted in the development of genetically male (XY) pigs with complete external and internal female genitalia, which, however, were significantly smaller than in 9-mo-old age-matched control females. Quantitative digital PCR analysis revealed a duplication of the SRY locus in Landrace pigs similar to the known palindromic duplication in Duroc breeds. Our study demonstrates the central role of the HMG domain in the SRY gene in male porcine sex determination. This proof-of-principle study could assist in solving the problem of sex preference in agriculture to improve animal welfare. Moreover, it establishes a large animal model that is more comparable to humans with regard to genetics, physiology, and anatomy, which is pivotal for longitudinal studies to unravel mammalian sex determination and relevant for the development of new interventions for human sex development disorders.
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http://dx.doi.org/10.1073/pnas.2008743118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812820PMC
January 2021

Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: results from the AMLSG 09-09 trial.

Blood 2020 Dec;136(26):3041-3050

Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.

Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P = .01). The better reduction in NPM1mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P = .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction in NPM1mut TLs across all treatment cycles, leading to a significantly lower relapse rate.
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http://dx.doi.org/10.1182/blood.2020005998DOI Listing
December 2020

Establishment and Characterization of a Sclerosing Spindle Cell Rhabdomyosarcoma Cell Line with a Complex Genomic Profile.

Cells 2020 12 11;9(12). Epub 2020 Dec 11.

Department of Orthopaedic Surgery, Eberhard Karls University Tuebingen, 72072 Tuebingen, Germany.

Sclerosing spindle cell rhabdomyosarcoma (SSRMS) is a rare rhabdomyosarcomas (RMS) subtype. Especially cases bearing a myogenic differentiation 1 () mutation are characterized by a high recurrence and metastasis rate, often leading to a fatal outcome. SSRMS cell lines are valuable in vitro models for studying disease mechanisms and for the preclinical evaluation of new therapeutic approaches. In this study, a cell line established from a primary SSRMS tumor of a 24-year-old female after multimodal chemotherapeutic pretreatment has been characterized in detail, including immunohistochemistry, growth characteristics, cytogenetic analysis, mutation analysis, evaluation of stem cell marker expression, differentiation potential, and tumorigenicity in mice. The cell line which was designated SRH exhibited a complex genomic profile, including several translocations and deletions. Array-comparative genomic hybridization (CGH) revealed an overall predominating loss of gene loci. The mesenchymal tumor origin was underlined by the expression of mesenchymal markers and potential to undergo adipogenic and osteogenic differentiation. Despite myogenic marker expression, terminal myogenic differentiation was inhibited, which might be elicited by the hotspot mutation. In vivo tumorigenicity could be confirmed after subcutaneous injection into NOD/SCID/γ mice. Summarized, the SRH cell line is the first adult SSRMS cell line available for preclinical research on this rare RMS subtype.
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http://dx.doi.org/10.3390/cells9122668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763666PMC
December 2020

Generation of two hiPSC clones (MHHi019-A, MHHi019-B) from a primary ciliary dyskinesia patient carrying a homozygous deletion in the NME5 gene (c.415delA (p.Ile139Tyrfs*8)).

Stem Cell Res 2020 10 7;48:101988. Epub 2020 Sep 7.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Germany. Electronic address:

Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by defects in motile cilia and is known to occur in about 1 in 20,000 live births (Horani and Ferkol, 2018). Among the many genes associated with PCD, NME5, a gene encoding a protein involved in ciliary function, was recently reported to be involved in PCD (Anderegg et al., 2019; Cho et al., 2020). We have established two human induced pluripotent stem cell clones from a PCD patient carrying a deletion in the NME5 gene (c.415delA (p.Ile139Tyrfs*8)).
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http://dx.doi.org/10.1016/j.scr.2020.101988DOI Listing
October 2020

IDH1/2 mutations in acute myeloid leukemia patients and risk of coronary artery disease and cardiac dysfunction-a retrospective propensity score analysis.

Leukemia 2020 Sep 18. Epub 2020 Sep 18.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany.

Clonal hematopoiesis of indeterminate potential (CHIP) is linked to leukemia gene mutations and associates with an increased risk for coronary artery disease and poor prognosis in ischemic cardiomyopathy. Two recurrently mutated genes in CHIP and adult acute myeloid leukemia (AML) encode for isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). Global expression of mutant IDH2 in transgenic mice-induced dilated cardiomyopathy and muscular dystrophy. In this retrospective observational study, we investigated whether mutant IDH1/2 predisposes to cardiovascular disease in AML patients. Among 363 AML patients, IDH1 and IDH2 mutations were detected in 26 (7.2%) and 39 patients (10.7%), respectively. Mutant IDH1 patients exhibited a significantly higher prevalence of coronary artery disease (26.1% vs. 6.4%, p = 0.002). Applying inverse probability-weighting analysis, patients with IDH1/2 mutations had a higher risk for a declining cardiac function during AML treatment compared to IDH1/2 wild type patients [left ventricular ejection fraction pretreatment compared to 10 months after diagnosis: 59.2% to 41.9% (p < 0.001) vs 58.5% to 55.4% (p = 0.27), respectively]. Mechanistically, RNA sequencing and immunostaining in hiPS-derived cardiomyocytes indicated that the oncometabolite R-2HG exacerbated doxorubicin mediated cardiotoxicity. Evaluation of IDH1/2 mutation status may therefore help identifying AML patients at risk for cardiovascular complications during cytotoxic treatment.
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http://dx.doi.org/10.1038/s41375-020-01043-xDOI Listing
September 2020

Histiocytic sarcoma progressing from follicular lymphoma and mimicking acquired hemophagocytic lymphohistiocytosis.

Ann Hematol 2020 Oct 17;99(10):2441-2443. Epub 2020 Aug 17.

Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg-Str.1, 30625, Hannover, Germany.

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http://dx.doi.org/10.1007/s00277-020-04190-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481156PMC
October 2020

Risk of tumor lysis syndrome in patients with acute myeloid leukemia treated with venetoclax-containing regimens without dose ramp-up.

Ann Hematol 2021 Feb 23;100(2):595-599. Epub 2020 Jul 23.

Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Straße 1, 30625, Hannover, Germany.

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http://dx.doi.org/10.1007/s00277-020-04181-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817590PMC
February 2021

De novo missense variants in the RAP1B gene identified in two patients with syndromic thrombocytopenia.

Clin Genet 2020 10 21;98(4):374-378. Epub 2020 Jul 21.

Department of Human Genetics, Hannover Medical School, Hanover, Germany.

We present two independent cases of syndromic thrombocytopenia with multiple malformations, microcephaly, learning difficulties, dysmorphism and other features. Exome sequencing identified two novel de novo heterozygous variants in these patients, c.35G>T p.(Gly12Val) and c.178G>C p.(Gly60Arg), in the RAP1B gene (NM_001010942.2). These variants have not been described previously as germline variants, however functional studies in literature strongly suggest a clinical implication of these two activating hot spot positions. We hypothesize that pathogenic missense variants in the RAP1B gene cause congenital syndromic thrombocytopenia with a spectrum of associated malformations and dysmorphism, possibly through a gain of function mechanism.
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http://dx.doi.org/10.1111/cge.13807DOI Listing
October 2020

Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency.

Leukemia 2020 10 18;34(10):2673-2687. Epub 2020 Jun 18.

Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.
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http://dx.doi.org/10.1038/s41375-020-0899-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515837PMC
October 2020

Generation of two human induced pluripotent stem cell lines (MHHi017-A, MHHi017-B) from a patient with primary ciliary dyskinesia carrying a homozygous mutation (c.7915C > T [p.Arg2639*]) in the DNAH5 gene.

Stem Cell Res 2020 07 20;46:101848. Epub 2020 May 20.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Germany; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany.

Dynein axonemal heavy chain 5 (DNAH5) is part of a microtubule-associated protein complex found within the cilia of the lung. Mutations in the DNAH5 gene lead to impaired ciliary function and are linked to primary ciliary dyskinesia (PCD), a rare autosomal recessive disorder. We established two human induced pluripotent stem cell (hiPSC) lines generated from a patient with PCD and homozygous mutation in the corresponding DNAH5 gene. These cell lines represent an excellent tool for modeling the ciliary dysfunction in PCD.
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http://dx.doi.org/10.1016/j.scr.2020.101848DOI Listing
July 2020

Generation of two hiPSC lines (MHHi016-A, MHHi016-B) from a primary ciliary dyskinesia patient carrying a homozygous 5 bp duplication (c.248_252dup (p.Gly85Cysfs*11)) in exon 1 of the CCNO gene.

Stem Cell Res 2020 07 18;46:101850. Epub 2020 May 18.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Germany.

Cyclin O (CCNO) is involved in cell cycle regulation and mutations of CCNO are linked to the rare genetic disease primary ciliary dyskinesia (PCD). Mutations in CCNO are associated with reduced cilia number and cilia agenesis on epithelia of the respiratory tract. This article deals with the description of two hiPSC lines generated from a PCD patient carrying a mutation in exon 1 of the CCNO gene. The lines offer a valuable tool for in vitro modeling PCD pathophysiology.
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http://dx.doi.org/10.1016/j.scr.2020.101850DOI Listing
July 2020

and Interspecies Chimera Assay Using Early Pig Embryos.

Cell Reprogram 2020 06 19;22(3):118-133. Epub 2020 May 19.

Institute of Farm Animal Genetics, Friedrich-Loeffler-Institut, Neustadt, Germany.

Chimeric pigs harboring organs derived from human stem cells are promising for patient-specific regenerative therapies. Induced pluripotent stem cells (iPSCs) can contribute to all cell types of the fetus, including germline after injection into embryos. However, ethical concerns prohibit testing human iPSCs in chimera assays. Here, we evaluated porcine embryos as hosts for an interspecies chimera assay using iPSCs from either cynomolgus monkeys (cyiPSCs) or mouse (miPSCs). To establish an culture system compatible for cyiPSCs and porcine embryos, we determined blastocyst development in eight different stem cell media. The highest developmental rates of blastocysts were achieved in Knockout Dulbecco's modified Eagle's medium with 20% knockout serum replacement. We found that cyiPSCs injected into porcine embryos survived and were mostly located in the trophectoderm (TE). Instead, when miPSCs were injected into porcine embryos, the cells rapidly proliferated. The behavior of chimeras developed was recapitulated ; cyiPSCs were observed in the TE, but not in the porcine epiblast. However, when miPSCs were injected into derived porcine embryos, mouse cells were found in both, the epiblast and TE. These results demonstrate that porcine embryos could be useful for evaluating the interspecies chimera-forming ability of iPSCs from different species.
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http://dx.doi.org/10.1089/cell.2019.0107DOI Listing
June 2020

Generation of an induced pluripotent stem cell line (MHHi018-A) from a patient with Cystic Fibrosis carrying p.Asn1303Lys (N1303K) mutation.

Stem Cell Res 2020 04 25;44:101744. Epub 2020 Mar 25.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), REBIRTH-Research Center for Translational and Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), 30625 Hannover, Germany.

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene which encodes for a chloride ion channel regulating the balance of salt and water across secretory epithelia. Here we generated an iPSC line from a CF patient homozygous for the p.Asn1303Lys mutation, a Class II folding defect mutation. This iPSC line provides a useful resource for disease modeling and to investigate the pharmacological response to CFTR modulators in iPSC derived epithelia.
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http://dx.doi.org/10.1016/j.scr.2020.101744DOI Listing
April 2020

Implementation of RNA sequencing and array CGH in the diagnostic workflow of the AIEOP-BFM ALL 2017 trial on acute lymphoblastic leukemia.

Ann Hematol 2020 Apr 20;99(4):809-818. Epub 2020 Feb 20.

Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Risk-adapted therapy has significantly contributed to improved survival rates in pediatric acute lymphoblastic leukemia (ALL) and reliable detection of chromosomal aberrations is mandatory for risk group stratification. This study evaluated the applicability of panel-based RNA sequencing and array CGH within the diagnostic workflow of the German study group of the international AIEOP-BFM ALL 2017 trial. In a consecutive cohort of 117 children with B cell precursor (BCP) ALL, array analysis identified twelve cases with an IKZF1 profile of gene deletions and one case of masked hypodiploidy. Genetic markers BCR-ABL1 (n = 1), ETV6-RUNX1 (n = 25), and rearrangements involving KMT2A (n = 3) or TCF3 (n = 3) were assessed by established conventional techniques such as karyotyping, FISH, and RT-PCR. Comparison of these results with RNA sequencing analysis revealed overall consistency in n=115/117 cases, albeit with one undetected AFF1-KMT2A fusion in RNA sequencing and one undetected ETV6-RUNX1 fusion in conventional analyses. The combined application of RNA sequencing, FISH, and CGH+SNP array reliably detected all genetic markers necessary for risk stratification and will be used as the diagnostic standard workflow for BCP-ALL patients enrolled in the AIEOP-BFM ALL 2017 study. Prospectively, consistent collection of genome-wide CGH+SNP array as well as RNA sequencing data will be a valuable source to elucidate new prognostic lesions beyond established markers of pediatric ALL. In this respect, RNA sequencing identified various gene fusions in up to half of the IKZF1 (n = 6/12) and B-other (n = 19/36) cases but not in cases with hyperdiploid karyotypes (n = 35). Among these fusions, this study reports several previously undescribed in frame PAX5 fusions, including PAX5-MYO1G and PAX5-NCOA6.
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http://dx.doi.org/10.1007/s00277-020-03953-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069912PMC
April 2020

Generation of three induced pluripotent stem cell lines (MHHi012-A, MHHi013-A, MHHi014-A) from a family with Loeys-Dietz syndrome carrying a heterozygous p.M253I (c.759G>A) mutation in the TGFBR1 gene.

Stem Cell Res 2020 03 4;43:101707. Epub 2020 Feb 4.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; REBIRTH-Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Germany.

Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder characterized by a genetic predisposition for thoracic aortic aneurysm and dissection. Despite heterozygous loss-of-function mutations in genes for ligand, receptor, or downstream mediators of the transforming growth factor β (TGFβ) pathway, LDS is associated with a signature of high TGFβ signaling. We generated induced pluripotent stem cell (iPSC) lines from three adult LDS-patients (two male, one female) of a family with a heterozygous point mutation in exon 4 of the TGFβ-receptor1 (TGFBR1) gene (p.M253I; c.759G>A). The lines offer a valuable resource for modeling the pathophysiology of genetically mediated aortic disease.
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http://dx.doi.org/10.1016/j.scr.2020.101707DOI Listing
March 2020

Human STAT1 gain-of-function iPSC line from a patient suffering from chronic mucocutaneous candidiasis.

Stem Cell Res 2020 03 17;43:101713. Epub 2020 Jan 17.

JRG Translational Hematology of Congenital Diseases, Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany; REBIRTH-Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany. Electronic address:

Chronic mucocutaneous candidiasis (CMC) is a disease that is characterized by susceptibility to chronic or recurrent infections with Candida spp. due to mutations affecting mainly the IL-17 signaling of T-Cells. The most common etiologies of CMC are gain-of-function (GOF) mutations in the STAT1 gene. In this paper we report the generation of a hiPSC line from a patient suffering from CMC due to a heterozygous GOF STAT1 p.R274Q mutation which can be used for disease modeling purposes.
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http://dx.doi.org/10.1016/j.scr.2020.101713DOI Listing
March 2020

Induced pluripotent stem cell line (PEIi003-A) derived from an apparently healthy male individual.

Stem Cell Res 2020 01 4;42:101679. Epub 2019 Dec 4.

Host‑Pathogen Interactions, Paul-Ehrlich-Institut, 63225 Langen, Germany; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address:

Induced pluripotent stem cells (iPSCs) are a useful tool to investigate pathomechanistic and cellular processes due to their differentiation potential into different somatic cell types in vitro. Here, we have generated iPSCs from an apparently healthy male individual using an integration-free reprogramming method. The resulting iPSCs are pluripotent and display a normal karyotype. Furthermore, we demonstrate that this iPSC line can be differentiated into all three germ layers.
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http://dx.doi.org/10.1016/j.scr.2019.101679DOI Listing
January 2020

Generation of a NKX2.1 - p63 double transgenic knock-in reporter cell line from human induced pluripotent stem cells (MHHi006-A-4).

Stem Cell Res 2020 01 19;42:101659. Epub 2019 Nov 19.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; REBIRTH-Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Germany. Electronic address:

Tumor protein p63 (p63) encodes for a transcription factor of the p53 family and is a marker for respiratory basal cells. Based on a NKX2.1 knock-in reporter cell line from human induced pluripotent stem cells (hiPSCs) (MHHi06-A-2) we established a NKX2.1/p63 double transgenic knock-in reporter cell line using TALEN technology. The reporter enables the optimization and monitoring of hiPSC differentiation towards NKX2.1/p63 double positive cells as well as enrichment for single or double positive cells.
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http://dx.doi.org/10.1016/j.scr.2019.101659DOI Listing
January 2020

Induced pluripotent stem cells (iPSCs) derived from a renpenning syndrome patient with c.459_462delAGAG mutation in PQBP1 (PEIi001-A).

Stem Cell Res 2019 12 15;41:101592. Epub 2019 Oct 15.

Host‑Pathogen Interactions, Paul-Ehrlich-Institut, Langen 63225, Germany; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address:

The Renpenning syndrome spectrum is a rare X-linked mental retardation syndrome characterized by intellectual disability, microcephaly, low stature, lean body and hypogonadism. Mutations in the polyglutamine tract binding protein 1 (PQBP1) locus are causative for disease. Here, we describe the generation of an iPSC line from a patient mutated in the polar amino acid-rich domain of PQBP1 resulting in a C-terminal truncated protein (c.459_462 delAGAG, type p.R153fs193X).
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http://dx.doi.org/10.1016/j.scr.2019.101592DOI Listing
December 2019

Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols.

Haematologica 2020 Jul 10;105(7):1887-1894. Epub 2019 Oct 10.

Clinica Pediatrica and Centro Ricerca Tettamanti, Università di Milano-Bicocca, Fondazione MBBM/S.Gerardo Hospital, Monza, Italy.

ABL-class fusions other than characterize around 2-3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than treated according to AIEOP-BFM (Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor (TKI) during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of ≥5×10 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases, the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality (TRM) 20.8+6.8%. One out of 13 cases with TKI added to chemotherapy relapsed while eight of 33 cases without TKI treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high TRM (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of TKI, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (Registered at: .
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http://dx.doi.org/10.3324/haematol.2019.231720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327633PMC
July 2020

Generation of a CFTR knock-in reporter cell line (MHHi006-A-1) from a human induced pluripotent stem cell line.

Stem Cell Res 2019 10 20;40:101542. Epub 2019 Aug 20.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; REBIRTH-Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Germany. Electronic address:

CFTR encodes for a chloride ion channel expressed primarily in secretory epithelia in the airways, intestine, liver and other tissues. Mutations in the CFTR gene have been identified in people suffering from Cystic Fibrosis. Here, we established a CFTR knock-in reporter cell line from a human iPSC line (MHHi006-A) using TALEN technology. The reporter enables the monitoring and optimization of the differentiation of pluripotent stem cells into CFTR expressing epithelia on a single cell level, as well as the enrichment of CFTR positive cells, which represent an excellent tool for Cystic Fibrosis disease modelling, drug screening and ultimately cellular therapies.
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http://dx.doi.org/10.1016/j.scr.2019.101542DOI Listing
October 2019

Generation of a NKX2.1 knock-in reporter cell line from human induced pluripotent stem cells (MHHi006-A-2).

Stem Cell Res 2019 08 28;39:101492. Epub 2019 Jun 28.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; REBIRTH-Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Germany.

NK homeobox 1 (NKX2.1; also known as thyroid transcription factor 1, TTF-1) encodes for a transcription factor involved in the development of thyroid, lung and brain. Here, we established a NKX2.1 knock-in reporter cell line from human induced pluripotent stem cells (iPSCs) using TALEN technology. The reporter enables the optimization and monitoring of the differentiation of pluripotent stem cells (PSCs) into NKX2.1 expressing cells on a single cell level, as well as the enrichment of NKX2.1 positive cells.
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http://dx.doi.org/10.1016/j.scr.2019.101492DOI Listing
August 2019

Clonal evolution patterns in acute myeloid leukemia with NPM1 mutation.

Nat Commun 2019 05 2;10(1):2031. Epub 2019 May 2.

Department of Internal Medicine III, University Hospital of Ulm, Ulm, 89081, Germany.

Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To characterize the genetic composition of NPM1 mutated (NPM1) AML, we assess mutation status of five recurrently mutated oncogenes in 129 paired NPM1 samples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1 loss (n = 11). To better understand these NPM1 loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1 loss patients (pts) feature distinct mutational patterns that share almost no somatic mutation with the corresponding diagnosis sample and impact different signaling pathways. In contrast, profiles of pts with persistent NPM1 are reflected by a high overlap of mutations between diagnosis and relapse. Our findings confirm that relapse often originates from persistent leukemic clones, though NPM1 loss cases suggest a second "de novo" or treatment-associated AML (tAML) as alternative cause of relapse.
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http://dx.doi.org/10.1038/s41467-019-09745-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497712PMC
May 2019

Comprehensive analysis of isolated der(1;7)(q10;p10) in a large international homogenous cohort of patients with myelodysplastic syndromes.

Genes Chromosomes Cancer 2019 10 30;58(10):689-697. Epub 2019 Apr 30.

Clinics of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.

The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the new comprehensive cytogenetic scoring system for MDS, chromosome 7 anomalies are no longer generally assigned to poor risk features but are thoroughly separated. However, der(1;7)(q10;p10), hereinafter der(1;7), is merged into the group labeled "any other single" and belongs to the intermediate risk group, just by definition due to lack of adequate clinical data. The aim of our international collaborative was to clarify the "real" prognostic impact of der(1;7) on a homogenous and well-documented data base. We performed detailed analysis of 63 MDS patients with isolated der(1;7) constituting the largest cohort hitherto reported. Furthermore, clinical data are compared with those of patients with isolated del(7q) and isolated monosomy 7. Median overall survival (OS) of patients with der(1;7) is 26 months (hazard ratio (HR) 0.91 for del(7q) vs der(1;7) and 2.53 for monosomy 7 vs der(1;7)). The der(1;7) is associated with profound thrombocytopenia most probably causing the reduced OS which is in striking contrast to the low risk for AML transformation (HR 3.89 for del(7q) vs der(1;7) and 5.88 for monosomy 7 vs der(1;7)). Molecular karyotyping indicates that der(1;7) is generated in a single step during mitosis and that a chromosomal imbalance rather than a single disrupted gene accounts for malignancy. Thus, the current cytogenetic scoring system assigning isolated der(1;7) to the intermediate risk group is now confirmed by a sufficient data set.
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http://dx.doi.org/10.1002/gcc.22760DOI Listing
October 2019

Generation of an induced pluripotent stem cell (iPSC) line, DHMCi005-A, from a patient with CALFAN syndrome due to mutations in SCYL1.

Stem Cell Res 2019 05 22;37:101428. Epub 2019 Mar 22.

Centre for Child and Adolescent Medicine, Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany. Electronic address:

Variants in SCYL1 can cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN). The encoded protein is involved in intracellular trafficking between Golgi and ER, specific mechanisms are still to be elucidated. We reprogrammed fibroblasts of a 2 years old male patient with CALFAN Syndrome due to a homozygous nonsense variant in SCYL1 (c.[1882C > T]; c.[1882C > T]/p.[Gln628*]; p.[Gln628*]) and generated DHMCi005-A using the Cytotune®-iPS 2.0 Sendai Reprogramming Kit (Invitrogen). Cells showed a normal karyotype. Pluripotency was proven using immunohistochemistry, RT-PCR, and flow cytometry. Differentiation into all germ layers was shown using the STEMdiff™ Trilineage Differentiation Kit (Stemcell Technologies).
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http://dx.doi.org/10.1016/j.scr.2019.101428DOI Listing
May 2019