Papers by Elisabeth Oppliger Leibundgut
Blood, 2002
The most frequent chromosomal aberrations in B-cell chronic lymphocytic leukemia (B-CLL) are dele... more The most frequent chromosomal aberrations in B-cell chronic lymphocytic leukemia (B-CLL) are deletions on 13q, 11q, and 17p, and trisomy 12, all of which are of prognostic significance. Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) are used for their detection, but cytogenetic analysis is hampered by the low mitotic index of B-CLL cells, and FISH depends on accurate information about candidate regions. We used a set of 400 highly informative microsatellite markers covering all chromosomal arms (allelotyping) and automated polymerase chain reaction (PCR) protocols to screen 46 patients with typical B-CLL for chromosomal aberrations. For validation, we compared data with our conventional karyotype results and fine mapping with conventional single-site PCR. All clonal cytogenetic abnormalities potentially detectable by our microsatellite PCR (eg, del13q14 and trisomy 12) were picked up. Allelotyping revealed additional complex aberrations in patients w...
Haematologica, 2005
Previous studies using flow cytometry have shown that CD34+ cell trafficking is increased in pati... more Previous studies using flow cytometry have shown that CD34+ cell trafficking is increased in patients with chronic idiopathic myelofibrosis. Few data exist on physiologic CD34 + cell trafficking and the quantification of very low cell ranges requires reliable and sensitive measurement techniques. The aim of this study was to establish a quantitative polymerase chain reaction (PCR) technique for studying CD34+ cell trafficking in physiologic conditions, and in patients with myeloproliferative diseases. CD34+ cell trafficking was measured in 56 controls [(healthy controls (n=21), patients with ischemic cardiopathy (n=21), patients with secondary thrombocytosis or erythrocytosis (n=14)], and in 37 untreated patients with myeloproliferative diseases diagnosed according to the WHO-criteria [(essential thrombocythemia (n=10), polycythemia vera (n=14) and chronic idiopathic myelofibrosis (n=13)]. Quantitative PCR was used to determine CD34 mRNA expression in peripheral blood samples. Physi...
Human Genetics, 1995
Ornithine transcarbamylase (OTC) deficiency, the most common inborn error of the urea cycle, show... more Ornithine transcarbamylase (OTC) deficiency, the most common inborn error of the urea cycle, shows an X-linked inheritance with frequent new mutations. Investigations of patients with OTC deficiency have indicated an overproportionate share of mutations at CpG dinucleotides. These statistics may, however, be biased because of the easy detection of CpG mutations by screening for TaqI and MspI restriction sites. In the present study, we investigated 30 patients, with diagnosed OTC deficiency, for new sites with an increased probability of mutation by complete DNA sequence analysis of all ten exons of the OTC gene. In six patients, two codons in exons 2 and 5, respectively, contained novel recurrent mutations, all of them affecting CpG dinucleotides. They included C to T and G to A transitions in codon 40, changing an arginine to cysteine and histidine, respectively, and a C to T transition in codon 178 causing the substitution of threonine by methionine. The first two mutations were characterized by a mild clinical course with high risk of sudden death in late childhood or early adulthood, whereas the third mutation showed a more severe phenotypic expression. In addition to these novel mutations, we identified four patients with the known R277W mutation, making it the most common point mutation of the OTC gene.
New England Journal of Medicine, 2015
Imetelstat, a 13-mer oligonucleotide that is covalently modified with lipid extensions, competiti... more Imetelstat, a 13-mer oligonucleotide that is covalently modified with lipid extensions, competitively inhibits telomerase enzymatic activity. It has been shown to inhibit megakaryocytic proliferation in vitro in cells obtained from patients with essential thrombocythemia. In this phase 2 study, we investigated whether imetelstat could elicit hematologic and molecular responses in patients with essential thrombocythemia who had not had a response to or who had had unacceptable side effects from prior therapies. A total of 18 patients in two sequential cohorts received an initial dose of 7.5 or 9.4 mg of imetelstat per kilogram of body weight intravenously once a week until attainment of a platelet count of approximately 250,000 to 300,000 per cubic millimeter. The primary end point was the best hematologic response. Imetelstat induced hematologic responses in all 18 patients, and 16 patients (89%) had a complete hematologic response. At the time of the primary analysis, 10 patients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Molecular responses were seen in 7 of 8 patients who were positive for the JAK2 V617F mutation (88%; 95% confidence interval, 47 to 100). CALR and MPL mutant allele burdens were also reduced by 15 to 66%. The most common adverse events during treatment were mild to moderate in severity; neutropenia of grade 3 or higher occurred in 4 of the 18 patients (22%) and anemia, headache, and syncope of grade 3 or higher each occurred in 2 patients (11%). All the patients had at least one abnormal liver-function value; all persistent elevations were grade 1 or 2 in severity. Rapid and durable hematologic and molecular responses were observed in patients with essential thrombocythemia who received imetelstat. (Funded by Geron; ClinicalTrials.gov number, NCT01243073.).
Therapeutische Umschau. Revue thérapeutique, 2010
During the last 10 years several molecular markers have been established as useful tools among th... more During the last 10 years several molecular markers have been established as useful tools among the armamentarium of a hematologist. As a consequence, the number of performed hematologic molecular analyses has immensely increased. Often, such tests replace or complement other laboratory methods. Molecular markers can be useful in many ways: they can serve for diagnostics, describe the prognostic profile, predict which types of drugs are indicated, and can be used for the therapeutic monitoring of the patient to indicate an adequate response or predict resistance or relapse of the disease. Many markers fulfill more than one of these aspects. Most important, however, is the right choice of analyses at the right time-points!
Transfusion, 2011
Previous observations suggested recruitment of platelets (PLTs) and white blood cells (WBCs) duri... more Previous observations suggested recruitment of platelets (PLTs) and white blood cells (WBCs) during plateletpheresis and recruitment of hematopoietic progenitor cells (HPCs) by HPC apheresis. Quantification of recruitment helps to optimize yields and safety of these procedures; detection of WBC or HPC recruitment during plateletpheresis may further elucidate the mechanisms. This study was a prospective cohort study with 68 single-needle plateletpheresis donations (23 double, PLT yield ≥4.8 × 10(11) ; 23 triple, ≥7.2 × 10(11) ; 22 quadruple, ≥9.6 × 10(11) ). We measured PLTs, WBCs, WBC subpopulations, and circulating HPCs (CD34 mRNA) before, during, and after apheresis; calculated PLT recruitment and ratio of recruited to yielded PLT; and propose a novel concept to optimize the prediction of the PLT counts after apheresis (PLT(post) ). PLT recruitment (mean ± SD, 1.56 ± 0.31) caused a higher PLT(post) than predicted by the instrument (164 × 10(9) ± 23 × 10(9) vs. 111 × 10(9) ± 31 × 10(9) /L; p < 0.0001) in all three groups. The ratio of recruited to yielded PLT was 0.36 ± 0.15. The WBC count decreased by 9% to the time before rinse-back and returned to the baseline thereafter. No changes in circulating HPCs occurred. PLT recruitment during high-yield plateletpheresis facilitates the harvest of multiple PLT units in a single donation. The use of the ratio of recruited to yielded PLT may optimize the algorithm to predict PLT(post) . There was no recruitment of WBCs and HPCs during plateletpheresis. Therefore, the previously observed recruitment of HPCs during HPC apheresis seems to be related to other factors than the apheresis procedure itself.
The distinction of CLL from other mature B-cell neoplasms, especially from leukemic forms of mant... more The distinction of CLL from other mature B-cell neoplasms, especially from leukemic forms of mantle cell lymphoma or splenic marginal zone lymphoma, can be difficult but has important prognostic and therapeutic implications. We measured CLLU1 (CLL upregulated gene1) mRNA by qPCR and found a highly significant difference between CLL and other lymphoid neoplasms (AUC 0.96, 95%CI 0.93-0.99). Based on our cut-off values we can predict CLL and other mature B-cell neoplasms with high probability (PPV 99% and 94%). Analysis of CLLU1 expression is a rapid and reliable tool that may facilitate the diagnosis of mature B-cell neoplasms especially in inconclusive cases.
Leukemia Research, 2011
Kruppel-like factors KLF2 KLF3 KLF5 KLF6 Acute myeloid leukemia (AML) Acute promyelocytic leukemi... more Kruppel-like factors KLF2 KLF3 KLF5 KLF6 Acute myeloid leukemia (AML) Acute promyelocytic leukemia All-trans retinoic acid (ATRA) Neutrophil a b s t r a c t
Leukemia Research, 2010
Expression of N-myc downregulated gene 1 (NDRG1) is associated with growth arrest and differentia... more Expression of N-myc downregulated gene 1 (NDRG1) is associated with growth arrest and differentiation of tumor cells. In hematopoietic cells, NDRG1 was identified in a screen for differentiation-related genes in human myelomonocytic leukemic U937 cells. In the present study, we found significantly higher NDRG1 mRNA levels in granulocytes of healthy donors than in primary acute myeloid leukemia (AML) cells. Another NDRG family member, NDRG2, was significantly higher expressed in normal macrophages compared to primary AML cells. Moreover, NDRG1 mRNA levels increased in two acute promyelocytic leukemia (APL) patients as well as in NB4 and HT93 APL cells upon all-trans retinoic acid (ATRA) therapy. In line with these observations, silencing of NDRG1 diminished neutrophil differentiation of leukemic cell lines. In conclusion, we found an association of low NDRG1 levels with an immature cell phenotype and provide evidence that NDRG1 is functionally involved in neutrophil maturation.
Journal of Pediatric Hematology/Oncology, 2013
M.A. and S.L.: Designed the research and the article, drafted the article, and performed the anal... more M.A. and S.L.: Designed the research and the article, drafted the article, and performed the analysis; A.L.R., G.M.B., E.O.; N.A.P.; and L.M.: Performed experiments; M.A., S.L., and L.M.: Contributed to the retrieval of clinical data; all authors contributed to the interpretation of data and revised the manuscript critically. M.A. is scholar of the Telemaque foundation. The remaining authors declare no conflict of interest. Reprints
British Journal of Haematology, 2009
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Papers by Elisabeth Oppliger Leibundgut