Anna Jauch

evaplan at the University Hospital Heidelberg, Heidelburg, Baden-Württemberg, Germany

Are you Anna Jauch?

Claim your profile

Publications (239)1217.91 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The discovery of new targets for tailored therapy is a major improvement in oncology, and tools for the rapid and reliable detection of these targets are essential. Clinical trials demonstrated the benefit of recently developed antibodies against antigens on malignant B-cells. The aim of this study was to assess patients with plasma cell (PC) disorders for expression of antigens on malignant PCs that have exhibited promise in targeted cancer therapy. We retrospectively analyzed the expression of CD20, CD22, CD27, CD30, CD38, CD52, CD81, CD138 and SLAMF7 on PCs by flow cytometry in 103 patients with PC disorders. Furthermore, we studied cytogenetic data in order to correlate immunophenotyping and genetic parameters. The expression frequency of CD22, CD30 and CD52 was similar to other studies (12-35%, 0-19% and 0-8%, respectively). Unexpectedly, we observed a high CD20 expression frequency in 37% of all AL-amyloidosis cases. The presence of t(11;14) correlated positively with CD20 expression on PCs in AL-amyloidosis (p=0.018). Furthermore, the expression level of SLAMF7 was decreased in advanced PC disorders (p=0.025) and a diminished expression of SLAMF7 is associated with low expression of CD27 and CD81 on malignant PCs in newly diagnosed multiple myeloma. This study provides a contribution to targeted therapy options in PC disorders. Particularly, the results put an emphasis on CD20 as therapeutic target in AL-amyloidosis. Regarding the therapeutic options of the SLAMF7 antibody elotuzumab these data advise that analysis of SLAMF7 expression before application of elotuzumab might help to estimate the efficacy of elotuzumab in clinical trials. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · Cytometry Part B Clinical Cytometry

  • No preview · Article · Nov 2015 · Haematologica
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: microRNAs regulate gene-expression in biological and pathophysiological processes, including multiple myeloma. Here we address i) What are the number and magnitude of changes in miRNA-expression between normal plasma cells and myeloma- or MGUS-samples, and the latter two? ii) What is the biological relevance and how does miRNA-expression impact on gene-expression? iii) Is there a prognostic significance, and what is its background? Experimental design: Ninety-two purified myeloma-, MGUS-, normal plasma cell- and myeloma cell line-samples were investigated using miChip-arrays interrogating 559 human miRNAs. Impact on gene-expression was assessed by Affymetrix DNA-microarrays in two cohorts of myeloma patients (n = 677); chromosomal aberrations were assessed by iFISH, survival for 592 patients undergoing up-front high-dose chemotherapy. Results: Compared to normal plasma cells, 67/559 miRNAs (12%) with fold changes of 4.6 to -3.1 are differentially expressed in myeloma-, 20 (3.6%) in MGUS-samples, and three (0.5%) between MGUS and myeloma. Expression of miRNAs is associated with proliferation, chromosomal aberrations, tumor mass, and gene expression-based risk-scores. This holds true for target-gene signatures of regulated mRNAs. miRNA-expression confers prognostic significance for event-free and overall survival, as do respective target-gene signatures. Conclusions: The myeloma-miRNome confers a pattern of small changes of individual miRNAs impacting on gene-expression, biological functions, and survival.
    Full-text · Article · Oct 2015 · Oncotarget
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To assess associations between bone marrow infiltration patterns and localization in magnetic resonance imaging (MRI) and baseline clinical/prognostic parameters in multiple myeloma (MM). Methods: We compared baseline MM parameters, MRI patterns and localization of focal lesions to the mineralized bone in 206 newly diagnosed MM patients. Results: A high tumour mass (represented by International Staging System stage III) was significantly associated with severe diffuse infiltration (p = 0.015) and a higher number of focal lesions (p = 0.006). Elevated creatinine (p = 0.003), anaemia (p < 0.001) and high LDH (p = 0.001) correlated with severe diffuse infiltration. A salt and pepper diffuse pattern had a favourable prognosis. A higher degree of destruction of mineralized bone (assessed by X-ray or computed tomography) was associated with an increasing number of focal lesions on MRI (p < 0.001). Adverse cytogenetics (del17p/gain1q21/t(4;14)) were associated with diffuse infiltration (p = 0.008). The presence of intraosseous focal lesions exceeding the mineralized bone had a borderline significant impact on prognosis. Conclusions: Diffuse bone marrow infiltration on MRI correlates with adverse cytogenetics, lowered haemoglobin values and high tumour burden in newly diagnosed MM whereas an increasing number of focal lesions correlates with a higher degree of bone destruction. Focal lesions exceeding the cortical bone did not adversely affect the prognosis. Key points: • Diffuse MRI correlates with adverse cytogenetics, lowered haemoglobin and high tumour burden. • Higher numbers of MRI focal lesions correlate with increasing degree of bone destruction. • Focal lesions exceeding the cortical bone borderline significantly influence survival. • Moderate/severe diffuse infiltration and more than 23 focal lesions adversely affect survival.
    No preview · Conference Paper · Sep 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aim of this prospective study was to investigate prognostic significance of increased bone marrow microcirculation as detected by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for survival and local complications in patients with multiple myeloma (MM). We performed DCE-MRI of the lumbar spine in 131 patients with newly diagnosed MM and analysed data according to the Brix model to acquire amplitude A and exchange rate constant k ep. In 61 patients a second MRI performed after therapy was evaluated to assess changes in vertebral height and identify vertebral fractures. Correlation analysis revealed significant positive association between beta2-microglobulin as well as immunoparesis with DCE-MRI parameters A and k ep. Additionally, A was negatively correlated with haemoglobin levels and k ep was positively correlated with LDH levels. Higher baseline k ep values were associated with decreased vertebral height in a second MRI (P = 0.007) and A values were associated with new vertebral fractures in the lower lumbar spine (P = 0.03 for L4). Pre-existing lytic bone lesions or remission after therapy had no impact on the occurrence of vertebral fractures. Multivariate analysis revealed that amplitude A is an independent adverse risk factor for overall survival. DCE-MRI is a non-invasive tool with significance for systemic prognosis and vertebral complications. • Qualitative parameters from DCE-MRI are correlated with established factors of disease activity • Increased marrow microcirculation might be a risk factor for loss of vertebral height and fractures • Amplitude A is an independent predictor for shortened overall survival.
    Full-text · Article · Jul 2015 · European Radiology

  • No preview · Article · Jun 2015 · Cytotherapy
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine the minimal set of genetic alterations required for the development of a very low risk clinically symptomatic gastro-intestinal stromal tumour within the stomach wall. We studied the genome of a very low-risk gastric gastro-intestinal stromal tumour by whole-genome sequencing, comparative genomic hybridisation and methylation profiling. The studied tumour harboured two typical genomic lesions: loss of the long arm of chromosome 14 and an activating mutation in exon 11 of KIT. Besides these genetic lesions, only two point mutations that may affect tumour progression were identified: A frame-shift deletion in RNF146 and a missense mutation in a zinc finger of ZNF407. Whilst the frameshift deletion in RNF146 seemed to be restricted to this particular tumour, a similar yet germline mutation in ZNF407 was found in a panel of 52 gastro-intestinal stromal tumours from different anatomical sites and different categories. Germline polymorphisms in the mitotic checkpoint proteins Aurora kinase A and BUB1 kinase B may have furthered tumour growth. The epigenetic profile of the tumour matches that of other KIT-mutant tumours. We have identified mutations in three genes and loss of the long arm of chromosome 14 as the so far minimal set of genetic abnormalities sufficient for the development of a very low risk clinically symptomatic gastric stromal tumour.
    Preview · Article · Jun 2015 · PLoS ONE
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hairy cell leukemia (HCL) is marked by near 100% mutational frequency of BRAFV600E mutations. Recurrent cooperating genetic events that may contribute to HCL pathogenesis or affect clinical course in HCL are currently not described. We therefore performed whole exome sequencing to explore the mutational landscape of purine analogue refractory HCL. In addition to the disease defining BRAFV600E mutations, we identified mutations in EZH2, ARID1A and recurrent inactivating mutations of the cell cycle inhibitor CDKN1B (p27). Targeted deep sequencing of CDKN1B in a larger cohort of HCL patients identify deleterious CDKN1B mutations in 16% of patients with HCL (n=13/81). In 11 of 13 patients the CDKN1B mutation was clonal, implying an early role of CDKN1B mutations in the pathogenesis of HCL. CDKN1B mutations were not found to impact clinical characteristics or outcome in this cohort. These data identify HCL as having the highest frequency of CDKN1B mutations amongst cancers and identify CDKN1B as the 2nd most commonly mutated gene in HCL. Moreover, given the known function of CDNK1B, these data suggest a novel role for alterations in regulation of cell cycle and senescence in HCL with CDKN1B mutations. Copyright © 2015 American Society of Hematology.
    No preview · Article · Jun 2015 · Blood
  • [Show abstract] [Hide abstract]
    ABSTRACT: Interstitial deletions encompassing chromosome bands 1p32.1p32.3 are rare. Only nine unrelated patients with partially overlapping 1p32.1p32.3 deletions of variable size and position have been reported to date. We report on a 17-month-old boy with choanal atresia, hearing loss, urogenital anomalies, and microcephaly in whom an interstitial de novo deletion of 6.4 Mb was detected in 1p32.1p32.3 (genomic position chr1:54,668,618-61,113,264 according to GRCh37/hg19). The deleted region harbors 31 RefSeq genes. Notable genes in the region are PCSK9, haploinsufficiency of which caused low LDL cholesterol plasma levels in the patient, and DAB1, which is a candidate gene for cognitive deficits, microcephaly, and cerebral abnormalities such as ventriculomegaly and agenesis of the corpus callosum. Choanal atresia, microcephaly, and severe hearing loss were previously not known to be associated with 1p32 deletions. Our reported patient thus broadens the spectrum of clinical findings in this chromosome region and further facilitates genotype-phenotype correlations. Additional patients with overlapping deletions and/or point mutations in genes of this region need to be identified to elucidate the role of individual genes for the complex clinical manifestations. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Jun 2015 · American Journal of Medical Genetics Part A
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We report on a series of sequential events leading to long-term survival and cure of pediatric X-linked chronic granulomatous disease (X-CGD) patients after gamma-retroviral gene therapy (GT) and rescue HSCT. Due to therapy-refractory life-threatening infections requiring hematopoietic stem cell transplantation (HSCT) but absence of HLA-identical donors, we treated 2 boys with X-CGD by GT. Following GT both children completely resolved invasive Aspergillus nidulans infections. However, one child developed dual insertional activation of ecotropic viral integration site 1 (EVI1) and signal transducer and activator of transcription 3 (STAT3) genes, leading to myelodysplastic syndrome (MDS) with monosomy 7. Despite resistance to mismatched allo-HSCT with standard myeloablative conditioning, secondary intensified rescue allo-HSCT resulted in 100% donor chimerism and disappearance of MDS. The other child did not develop MDS despite expansion of a clone with a single insertion in the myelodysplasia syndrome 1 (MDS1) gene and was cured by early standard allo-HSCT. The slowly developing dominance of clones harboring integrations in MDS1-EVI1 may guide clinical intervention strategies, i.e. early rescue allo-HSCT, prior to malignant transformation. GT was essential for both children to survive and to clear therapy-refractory infections, and future GT with safer lentiviral self-inactivated (SIN) vectors may offer a therapeutic alternative for X-CGD patients suffering from life-threatening infections and lacking HLA-identical HSC donors.
    Full-text · Article · May 2015 · Current Gene Therapy
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations of the tumor suppressor p53 lead to chemotherapy resistance and a dismal prognosis in chronic lymphocytic leukemia (CLL). While p53 targets are used to identify patient subgroups with impaired p53 function, a comprehensive assessment of non-coding RNA targets of p53 in CLL is missing. We exploited the impaired transcriptional activity of mutant p53 to map out p53 targets in CLL by small RNA sequencing. We describe the landscape of p53-dependent miRNA/non-coding RNA induced in response to DNA damage in CLL. Besides the key p53 target miR-34a, we identify a set of p53-dependent miRNAs (miR-182-5p, miR-7-5p, miR-320c/d). In addition to miRNAs, the long non-coding RNAs (lncRNAs) NEAT1 and lincRNA-p21 are induced in response to DNA damage in the presence of functional p53 but not in CLL with p53 mutation. Induction of NEAT1 and lincRNA-p21 closely correlated to the induction of cell death after DNA damage. We used isogenic lymphoma cell line models to prove p53 dependence of NEAT1 and lincRNA-p21. The current work describes the p53-dependent miRNome and identifies lncRNAs NEAT1 and lincRNA-p21 as novel elements of the p53-dependent DNA damage response machinery in CLL and lymphoma.Leukemia accepted article preview online, 14 May 2015. doi:10.1038/leu.2015.119.
    Full-text · Article · May 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We investigated impact of subcutaneous versus intravenous bortezomib in the MM5 trial of the German-Speaking Myeloma Multicenter Group that compared bortezomib, doxorubicin, dexamethasone with bortezomib, cyclophosphamide, dexamethasone induction therapy in newly diagnosed multiple myeloma. Based on the data in relapsed myeloma, the route of administration for bortezomib was changed from intravenous to subcutaneous after 314 of 604 patients were enrolled. We analyzed 598 patients who received at least one dose of trial medication. Adverse events were reported more frequently in patients treated with intravenous bortezomib (intravenous=65%; subcutaneous=56%, p=0.02). Rates of peripheral neuropathy ≥ grade 2 were higher in patients treated with intravenous bortezomib during the third cycle (intravenous=8%; subcutaneous=2%, p=0.001). Overall response rates were similar in intravenously and subcutaneously treated patients. Presence of international staging system stage III, renal impairment or adverse cytogenetic abnormalities had no negative impact on overall response rates in both groups. This is to our knowledge the largest study to present data comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma. We show better tolerance and similar overall response rates for subcutaneous compared to intravenous bortezomib. The clinical trial is registered at as No. 2010-019173-16. Copyright © 2015, Ferrata Storti Foundation.
    Full-text · Article · Apr 2015 · Haematologica
  • [Show abstract] [Hide abstract]
    ABSTRACT: Diffuse and focal bone marrow infiltration patterns detected by magnetic resonance imaging have been shown to be of prognostic significance in all stages of monoclonal plasma cell disorders and have therefore been incorporated into the definition of the disease. The aim of this retrospective analysis was to develop a rapidly evaluable prognostic scoring system, incorporating the most significant information acquired from magnetic resonance imaging. Therefore, the impact on progression-free and overall survival in 161 transplant-eligible myeloma patients was evaluated. Moderate/severe diffuse infiltration showed a negative prognostic impact on progression-free (p<0.001) and overall survival (p=0.003) compared to salt and pepper/minimal diffuse infiltration. A number of >25 focal lesions on whole-body or >7 on axial magnetic resonance imaging, were associated with an adverse prognosis (progression-free survival: p=0.001/0.003 and overall survival: p=0.04/0.02). A magnetic resonance imaging-based prognostic scoring system, combining grouped diffuse and focal infiltration patterns, was formulated and is applicable to whole-body as well as axial magnetic resonance imaging. The score identified high-risk patients with a median progression-free and overall survival of 23.4 and 55.9 months, respectively (whole-body-based). Multivariate analyses demonstrated that the magnetic resonance imaging-based prognostic score stage III (high-risk) and adverse cytogenetics remain as independent prognostic factors for both, progression-free and overall survival (whole-body-based, progression-free survival: hazard ratio=3.65, p<0.001; overall survival: hazard ratio=5.19, p=0.005). In conclusion, we suggest a magnetic resonance imaging-based prognostic scoring system which is a robust easy to assess and interpret parameter summarizing significant magnetic resonance imaging findings in transplant-eligible multiple myeloma patients. Copyright © 2015, Ferrata Storti Foundation.
    No preview · Article · Mar 2015 · Haematologica
  • [Show abstract] [Hide abstract]
    ABSTRACT: We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (≥VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma (MM) patients. VCD was found to be non-inferior to PAd with respect to ≥VGPR rates (37.0% vs. 34.3%, p=0.001). The rates of progressive disease (PD) were 0.4% (VCD) vs. 4.8% (PAd) (p=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ≥2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leucocytopenia/neutropenia (≥3°) occurred more frequently in the VCD arm (35.2% vs. 11.3%, p<0.001). Neuropathy rates (≥2°) were higher in the PAd group (14.9% vs. 8.4%, p=0.03). Serious Adverse Events (SAEs), both overall and those related to thromboembolic events, were higher in the PAd group (32.7% vs. 24.0%, p=0.04 and 2.8% vs. 0.4%, p=0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ≥VGPR rates with fewer PD and has a favorable toxicity profile. Therefore, VCD is preferable to PAd as induction therapy.Leukemia accepted article preview online, 19 March 2015. doi:10.1038/leu.2015.80.
    No preview · Article · Mar 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bortezomib has become a cornerstone in the treatment of AL amyloidosis. In this study, we addressed the prognostic impact of cytogenetic aberrations for bortezomib-treated patients. We analyzed a consecutive series of 101 patients with AL amyloidosis treated with bortezomib-dexamethasone as first-line treatment by interphase fluorescence in situ hybridization (iFISH). Patients were ineligible for high-dose chemotherapy, which would put them at risk for cardiac or renal failure, and thus represented a poor-risk group. Presence of t(11;14), versus its absence, was associated with inferior hematologic event-free survival (median, 3.4 v 8.8 months, respectively; P = .002), overall survival (median, 8.7 v 40.7 months, respectively; P = .05), and remission rate (≥ very good partial remission; 23% v 47%, respectively; P = .02). In multivariable Cox regression models incorporating established hematologic and clinical risk factors, t(11;14) was an independent adverse prognostic marker for hematologic event-free survival (hazard ratio, 2.94; 95% CI, 1.37 to 6.25; P = .006) and overall survival (hazard ratio, 3.13; 95% CI, 1.16 to 8.33; P = .03), but not for remission (≥ very good partial remission). Markedly, the multiple myeloma high-risk iFISH aberrations t(4;14), t(14;16), del(17p), and gain of 1q21 conferred no adverse prognosis in this bortezomib-dexamethasone-treated group. After backward variable selection, the final multivariable model was validated in a consecutive series of 32 patients treated with bortezomib, dexamethasone, and cyclophosphamide. iFISH results are important independent prognostic factors in AL amyloidosis. In contrast to our recently published results with melphalan and dexamethasone standard therapy, bortezomib is less beneficial to patients harboring t(11;14), whereas it effectively alleviates the poor prognosis inherent to high-risk aberrations. Given the discrepant response to different treatment modalities, iFISH may help to guide therapeutic choices in these poor-risk patients requiring rapid hematologic response. © 2015 by American Society of Clinical Oncology.
    Full-text · Article · Mar 2015 · Journal of Clinical Oncology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent ∼4.5 Mb microduplication of Xp11.22-p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22-p11.23, her phenotype and X-chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping ∼5 Mb duplication of Xp11.23-p11.3. Patient 4 showed a duplication of ∼5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a ∼8.5 Mb duplication Xp11.23-p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1-5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Mar 2015 · American Journal of Medical Genetics Part A
  • [Show abstract] [Hide abstract]
    ABSTRACT: Haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood cells. The accumulation of DNA damage in HSCs is a hallmark of ageing and is probably a major contributing factor in age-related tissue degeneration and malignant transformation. A number of accelerated ageing syndromes are associated with defective DNA repair and genomic instability, including the most common inherited bone marrow failure syndrome, Fanconi anaemia. However, the physiological source of DNA damage in HSCs from both normal and diseased individuals remains unclear. Here we show in mice that DNA damage is a direct consequence of inducing HSCs to exit their homeostatic quiescent state in response to conditions that model physiological stress, such as infection or chronic blood loss. Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs and, in the case of mice with a non-functional Fanconi anaemia DNA repair pathway, led to a complete collapse of the haematopoietic system, which phenocopied the highly penetrant bone marrow failure seen in Fanconi anaemia patients. Our findings establish a novel link between physiological stress and DNA damage in normal HSCs and provide a mechanistic explanation for the universal accumulation of DNA damage in HSCs during ageing and the accelerated failure of the haematopoietic system in Fanconi anaemia patients.
    No preview · Article · Feb 2015 · Nature
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Methods to isolate and culture primary prostate epithelial stem/progenitor cells (PESCs) have proven difficult and ineffective. Here, we present a method to grow and expand both murine and human basal PESCs long term in serum- and feeder-free conditions. The method enriches for adherent mouse basal PESCs with a Lin(-)SCA-1(+)CD49f(+)TROP2(high) phenotype. Progesterone and sodium selenite are additionally required for the growth of human Lin(-)CD49f(+)TROP2(high) PESCs. The gene-expression profiles of expanded basal PESCs show similarities to ESCs, and NF-kB function is critical for epithelial differentiation of sphere-cultured PESCs. When transplanted in combination with urogenital sinus mesenchyme, expanded mouse and human PESCs generate ectopic prostatic tubules, demonstrating their stem cell activity in vivo. This novel method will facilitate the molecular, genomic, and functional characterization of normal and pathologic prostate glands of mouse and human origin. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · Stem Cell Reports
  • [Show abstract] [Hide abstract]
    ABSTRACT: Compared with classical microscopic chromosome investigation, array diagnostics (molecular karyotyping) has the advantage of a much higher resolution (generally at least 100 kb as opposed to 5-10 Mb). It has become an indispensable method in the evaluation of psychomotor developmental disorders and intellectual disability. Chromosome aberrations actually represent the largest group (up to 25%) of identifiable causes of developmental disorders and comprise submicroscopic imbalances (microdeletions or -duplications) in 10-14% that cannot be detected by classical chromosome analysis. On the other hand, balanced chromosome aberrations which can be identified by microscopic analysis, and low-grade mosaic chromosomal disorders remain undetected by array methods. In many laboratories array diagnostics has become a first tier method in the evaluation of developmental disorders and classical chromosome investigations are no longer performed as the primary test. Array diagnostics is also used in the evaluation of e.g. short stature and multiple congenital anomalies. The identification of a chromosomal imbalance by array is followed by confirmation diagnostics and investigation of the parents, e.g. by regular chromosome and FISH analyses. In about 18%, structural chromosome aberrations are found that cannot be detected by array analysis alone. The most common array methods (array CGH, SNP array) are briefly introduced. Both the diagnostic possibilities and the restrictions of the method, as well as the pitfalls of interpretation of results are illustrated by case reports.
    No preview · Article · Jan 2015 · Padiatrische Praxis
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In order to understand the precise disease driving mechanisms in acute myeloid leukemia (AML), comparison of patient matched hematopoietic stem cells (HSC) and leukemia stem cells (LSC) is essential. In this analysis we have examined the value of aldehyde dehydrogenase (ALDH) activity in combination with CD34 expression for the separation of HSC from LSC in 104 patients with de novo AML. The majority of AML patients (80 out of 104) had low percentages of cells with high ALDH activity (ALDH+ cells) (<1.9%; ALDH-rare AML), whereas 24 patients had relatively numerous ALDH+ cells (≥1.9%; ALDH-numerous AML). In patients with ALDH-rare AML, normal HSC could be separated by their CD34+ALDH+ phenotype, whereas LSC were exclusively detected among CD34+ALDH- cells. For patients with ALDH-numerous AML, the CD34+ALDH+ subset consisted mainly of LSC and separation from HSC was not feasible. Functional analyses further showed that ALDH+ cells from ALDH-numerous AML were quiescent, refractory to ARA-C treatment and capable of leukemic engraftment in a xenogenic mouse transplantation model. Clinically, resistance to chemotherapy and poor long-term outcome were also characteristic for patients with ALDH-numerous AML providing an additional risk-stratification tool. The difference in spectrum and relevance of ALDH activity in the putative LSC populations demonstrates, in addition to phenotypic and genetic, also functional heterogeneity of leukemic cells and suggests divergent roles for ALDH activity in normal HSC versus LSC. By acknowledging these differences our study provides a new and useful tool for prospective identification of AML cases in which separation of HSC from LSC is possible. This article is protected by copyright. All rights reserved.
    Full-text · Article · Dec 2014 · International Journal of Cancer

Publication Stats

8k Citations
1,217.91 Total Impact Points


  • 2010-2015
    • evaplan at the University Hospital Heidelberg
      Heidelburg, Baden-Württemberg, Germany
    • National Center for Tumor Diseases (NCT) Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 1989-2015
    • Universität Heidelberg
      • • Institute of Human Genetics
      • • Department of Human Genetics
      Heidelburg, Baden-Württemberg, Germany
  • 2012
    • RWTH Aachen University
      • Institute of Human Genetics
      Aachen, North Rhine-Westphalia, Germany
  • 2002
    • Cedars-Sinai Medical Center
      • Division of Hematology and Oncology
      Los Ángeles, California, United States
  • 2001
    • Ludwig-Maximilians-University of Munich
      • Institute of Pathology
      München, Bavaria, Germany
  • 1999-2001
    • Maine Institute for Human Genetics and Health
      Бангор, Maine, United States
  • 1992
    • University of Florence
      Florens, Tuscany, Italy
    • Università degli Studi di Genova
      Genova, Liguria, Italy