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C Schoch

Publications and source records attributed to C Schoch.

At least 19 recordsLinked to original sources
PubMed2006

The MLL recombinome of acute leukemias.

Chromosomal rearrangements of the human MLL gene are a hallmark for aggressive (high-risk) pediatric, adult and therapy-associated acute leukemias. These patients need to be identified in order to subject these patients to appropriate therapy regimen. A recently developed long-distance inverse PCR method was applied to genomic DNA isolated from individual acute leukemia patients in order to identify chromosomal rearrangements of the human MLL gene. We present data of the molecular characterization of 414 samples obtained from 272 pediatric and 142 adult leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) was determined and several new TPGs were identified. The combined data of our study and published data revealed a total of 87 different MLL rearrangements of which 51 TPGs are now characterized at the molecular level. Interestingly, the four most frequently found TPGs (AF4, AF9, ENL and AF10) encode nuclear proteins that are part of a protein network involved in histone H3K79 methylation. Thus, translocations of the MLL gene, by itself coding for a histone H3K4 methyltransferase, are presumably not randomly chosen, rather functionally selected.

Acute Disease↗
PubMed2006

Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1-ETO.

AML1-ETO collaborates with further genetic abnormalities to induce acute myeloid leukaemia (AML). We analysed 99 patients with an AML1-ETO rearrangement for additional aberrations. Frequent genetic abnormalities were, loss of a sex chromosome (56/99, 56.5%) and del(9)(q22) (24/99, 24.2%). The most frequent molecular aberrations were mutations of KITD816 (3/23, 13%) and NRAS (8/89, 8.9%). Further molecular abnormalities were FLT3 mutations (3/87, 3.4%), AML1 (1/26, 3.8%) and PU1 (1/14, 7.1%). MLL-PTD, KRAS and CEBPA mutations were not found. These clinical findings support the model that AML1-ETO collaborates with other genetic alterations, such as mutations of receptor tyrosine kinases, to induce AML.

Acute Disease↗
PubMed2005

Towards a pathogenesis-oriented therapy of acute myeloid leukemia.

Genetic and molecular techniques have provided increasing insights into the biology of acute myeloid leukemia (AML). These investigations showed that AML is not a homogeneous disease but a heterogeneous group of biologically different subentities. These subentities are currently primarily defined by cytogenetics by which three main subgroups can be discriminated: AML with balanced translocations, AML with unbalanced aberrations and AML without cytogenetically detectable aberrations. Within the latter group molecular alterations are identified in more than half of cases such as NPM mutations, FLT3 mutations, MLL duplications and mutations of CEBP-alpha. The clinical meaning of these findings is illustrated by substantial differences in response to therapy and long-term outcome. As demonstrated by the recent multicenter trial of the German AML Cooperative Group (AMLCG) and other studies intensification of induction therapy may improve the results in distinct subtypes but fails to do so in others. Therefore, new strategies need to be explored which incorporate the knowledge about the biology of AML to develop biology adapted treatment strategies. This process has just begun and is predominantly determined by the availability of new agents and their evaluation in clinical phase I and II studies. A variety of targets are currently explored and some trials have yielded promising results already. The step towards a biology adapted treatment of AML is long and requires the combined efforts of researchers, clinicians and the pharmaceutical industry. The first steps towards this goal have been taken and give rise to the hope for more effective and more specific therapies of AML.

Combined Modality Therapy↗
PubMed2005

The t(8;17)(p11;q23) in the 8p11 myeloproliferative syndrome fuses MYO18A to FGFR1.

The 8p11 myeloproliferative syndrome (EMS) also known as stem cell leukemia-lymphoma syndrome (SCLL) is associated with translocations that disrupt FGFR1. The resultant fusion proteins are constitutively active tyrosine kinases, and different FGFR1 fusions are associated with subtly different disease phenotypes. We report here a patient with a t(8;17)(p11;q23) and an unusual myelodysplastic/myeloproliferative disease (MDS/MPD) characterized by thrombocytopenia due to markedly reduced size and numbers of megakaryocytes, with elevated numbers of monocytes, eosinophils and basophils. A novel mRNA fusion between exon 32 of the myosin XVIIIA gene (MYO18A) at chromosome band 17q11 and exon 9 of FGFR1 was identified. Partial characterization of the genomic breakpoints in combination of bubble-PCR with fluorescence in situ hybridization revealed that the t(8;17) arose from a three-way translocation with breaks at 8p11, 17q11 and 17q23. MYO18A-FGFR1 is structurally similar to other fusion tyrosine kinases and is likely to be the causative transforming lesion in this unusual MDS/MPD.

Aged↗
PubMed2005

New insights into MLL gene rearranged acute leukemias using gene expression profiling: shared pathways, lineage commitment, and partner genes.

Rearrangements of the MLL gene occur in both acute lymphoblastic and acute myeloid leukemias (ALL, AML). This study addressed the global gene expression pattern of these two leukemia subtypes with respect to common deregulated pathways and lineage-associated differences. We analyzed 73 t(11q23)/MLL leukemias in comparison to 290 other acute leukemias and demonstrate that 11q23 leukemias combined are characterized by a common specific gene expression signature. Additionally, in unsupervised and supervised data analysis algorithms, ALL and AML cases with t(11q23) segregate according to the lineage they are derived from, that is, myeloid or lymphoid, respectively. This segregation can be explained by a highly differing transcriptional program. Through the use of novel biological network analyses, essential regulators of early B cell development, PAX5 and EBF, were shown to be associated with a clear B-lineage commitment in lymphoblastic t(11q23)/MLL leukemias. Also, the influence of the different MLL translocation partners on the transcriptional program was directly assessed. Interestingly, gene expression profiling did not reveal a clear distinct pattern associated with one of the analyzed partner genes. Taken together, the identified molecular expression pattern of MLL fusion gene samples and biological networks revealed new insights into the aberrant transcriptional program in 11q23/MLL leukemias.

Acute Disease↗
PubMed2005

Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia.

In search for general PCR targets for minimal residual disease (MRD) studies in acute myeloid leukemia (AML), Wilms' tumor gene 1 (WT1) expression was assessed by real-time RT-PCR relative to the control gene ABL in 569 archived samples of AML patients (pts). Pts were analyzed at diagnosis (n=116) and during follow-up (n=105, median 4 times, range 2--17). Median follow-up time was 258 days (range 16--1578 days). In 66 pts, the WT1 expression was analyzed in comparison to a second PCR marker or to multiparameter flow cytometry. Quantitative WT1 levels correlated to the clinical course or a second marker in 83-96% of the cases. Prognostic significance of WT1 levels was analyzed at diagnosis and three intervals: (1) days 16--60, (2) days 61--120, and (3) days 121--180 after start of chemotherapy. Higher levels of WT1 expression were associated with shorter overall survival (OS) and event-free survival (EFS) within intervals 2 and 3 but not at diagnosis or interval 1. In addition, within these intervals, WT1/ABL levels <or=0.4% were associated with improved OS and EFS. An increase of WT1 levels was detected in 16/44 cases, which subsequently relapsed within a median of 38 days (range 8--180 days). In conclusion, quantification of WT1 may be used for MRD studies and for prognostification in AML.

Acute Disease↗
PubMed2005

Genomic gains and losses influence expression levels of genes located within the affected regions: a study on acute myeloid leukemias with trisomy 8, 11, or 13, monosomy 7, or deletion 5q.

We performed microarray analyses in AML with trisomies 8 (n=12), 11 (n=7), 13 (n=7), monosomy 7 (n=9), and deletion 5q (n=7) as sole changes to investigate whether genomic gains and losses translate into altered expression levels of genes located in the affected chromosomal regions. Controls were 104 AML with normal karyotype. In subgroups with trisomy, the median expression of genes located on gained chromosomes was higher, while in AML with monosomy 7 and deletion 5q the median expression of genes located in deleted regions was lower. The 50 most differentially expressed genes, as compared to all other subtypes, were equally distributed over the genome in AML subgroups with trisomies. In contrast, 30 and 86% of the most differentially expressed genes characteristic for AML with 5q deletion and monosomy 7 are located on chromosomes 5 or 7. In conclusion, gain of whole chromosomes leads to overexpression of genes located on the respective chromosomes. Losses of larger regions of the genome translate into lower expression of the majority of genes represented by only one allele. The reduced expression of these genes is the most characteristic difference in gene expression profiles between AML with monosomy 7 and AML with deletion 5q, respectively, and other AML subtypes. Therefore, these data provide evidence that gene dosage effects gene expression in AML with unbalanced karyotype abnormalities. Losses of specific regions of the genome determine the gene expression profile more strongly than the gain of whole chromosomes.

Chromosome Aberrations↗
PubMed2004

Discrimination of chronic lymphocytic leukemia (CLL) and CLL/PL by cytomorphology can clearly be correlated to specific genetic markers as investigated by interphase fluorescence in situ hybridization (FISH).

Although interphase fluorescence in situ hybridization (FISH) is routinely used in chronic lymphocytic leukemia (CLL), differences in the chromosomal pattern with respect to morphological subtypes of CLL (typical CLL, CLL/PL, PLL) are still under debate. We studied 153 patients with CLL and correlated cytomorphology on peripheral blood stains with FISH analysis and other prognostic markers. The percentage of prolymphocytes was calculated as a continuous variable and followed published thresholds in parallel while being correlated to FISH analysis. Higher percentages of prolymphocytes were associated significantly with deletion of 17p13. Deletion of 17p13 was most frequently observed in patients with more than 30% prolymphocytes. Trisomy 12 was found mainly in cases with 6-30% prolymphocytes. The percentage of prolymphocytes did not correlate with deletions of 11q23 or with 13q14 abnormalities. In conclusion, we suggest that further research focus on the percentage of prolymphocytes in CLL. Doing so, biologically relevant thresholds for the percentages of prolymphocytes in the peripheral blood and their association to underlying genetic markers could be investigated together with other biologically and especially prognostic markers.

Adult↗
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗
PubMed2004

Reduced-intensity conditioning using TBI (8 Gy), fludarabine, cyclophosphamide and ATG in elderly CML patients provides excellent results especially when performed in the early course of the disease.

Allogeneic bone marrow or stem cell transplantation is a curative therapeutic option for chronic myelogenous leukemia. In order to decrease the toxicity of the procedure, the dosage of total body irradiation was reduced from 12 to 8 Gy and subsequently the dose of cyclophosphamide from 120 to 80 mg/kg. The purine analogue fludarabine, ATG, cyclosporine A and a short course of methotrexate were given for immune suppression. So far, 35 elderly CML patients with sibling and unrelated donors have been transplanted. Transplant-related mortality at day + 100 was 11%. After engraftment, all patients achieved a complete cytogenetic remission. Relapse occurred in 14% of the patients. The risk of relapse was significantly higher in those patients transplanted in second chronic or accelerated phase (P = 0.048). After a median follow-up of 30 months (range 12-62), 63% of the patients are alive. Those patients transplanted within the first year from diagnosis had an overall survival of 79% (P = 0.049), emphasizing the benefit of early transplantation. Stepwise reduction of conditioning intensity resulted in stable engraftment, low relapse rates and encouraging overall survival in this high-risk patient group.

Antilymphocyte Serum↗
PubMed2004

Pediatric acute lymphoblastic leukemia (ALL) gene expression signatures classify an independent cohort of adult ALL patients.

Recent reports support a possible future application of gene expression profiling for the diagnosis of leukemias. However, the robustness of subtype-specific gene expression signatures has to be proven on independent patient samples. Here, we present gene expression data of 34 adult acute lymphoblastic leukemia (ALL) patients (Affymetrix U133A microarrays). Support Vector Machines (SVMs) were applied to stratify our samples based on given gene lists reported to predict MLL, BCR-ABL, and T-ALL, as well as MLL and non-MLL gene rearrangement positive pediatric ALL. In addition, seven other B-precursor ALL cases not bearing t(9;22) or t(11q23)/MLL chromosomal aberrations were analyzed. Using top differentially expressed genes, hierarchical cluster and principal component analyses demonstrate that the genetically more heterogeneous B-precursor ALL samples intercalate with BCR-ABL-positive cases, but were clearly distinct from T-ALL and MLL profiles. Similar expression signatures were observed for both heterogeneous B-precursor ALL and for BCR-ABL-positive cases. As an unrelated laboratory, we demonstrate that gene signatures defined for childhood ALL were also capable of stratifying distinct subtypes in our cohort of adult ALL patients. As such, previously reported gene expression patterns identified by microarray technology are validated and confirmed on truly independent leukemia patient samples.

Adult↗
PubMed2004

Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML.

The aim of this study was to compare the pattern of karyotype abnormalities of therapy-related acute myeloid leukemia (t-AML) (n=93) with de novo AML (n=1091), and to evaluate their impact on prognosis. Favorable, intermediate, and unfavorable cytogenetics were observed in 25.8, 28.0, and 46.2% of t-AML, and in 22.2, 57.3, and 20.4% of de novo AML. The median overall survival (OS) was shorter in t-AML than in de novo AML (10 vs 15 months, P=0.0007). Favorable and unfavorable cytogenetics had a prognostic impact with respect to OS in both t-AML (P=0.001 and 0.0001) and de novo AML (P<0.0001 and <0.0001). To define the overall prognostic impact of cytogenetics and t-AML, a multivariate Cox's regression analysis was performed for OS with favorable cytogenetics, unfavorable cytogenetics, t-AML, age, and white blood cell (WBC) count as covariates. All parameters proved to be independently related to OS (P=0.001 for t-AML, P<0.0001 for all other parameters). Within patients with t-AML, there were significant correlations between OS and both unfavorable (P<0.0001) and favorable cytogenetics (P=0.001), while age and WBC count had no impact on OS. In conclusion, these data indicate that cytogenetics are an important prognostic parameter in t-AML. Furthermore, t-AML is an unfavorable factor independent of cytogenetics with respect to survival.

Acute Disease↗