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Christoph Walz

Bio: Christoph Walz is an academic researcher from Ludwig Maximilian University of Munich. The author has contributed to research in topics: Imatinib mesylate & Fusion gene. The author has an hindex of 30, co-authored 71 publications receiving 3332 citations. Previous affiliations of Christoph Walz include Harvard University & Heidelberg University.


Papers
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Journal ArticleDOI
TL;DR: It is concluded that human autoantigen pericentriolar material (PCM1)-JAK2 is a novel, recurrent fusion gene in hematologic malignancies and patients with PCM1- JAK2 disease are attractive candidates for targeted signal transduction therapy.
Abstract: We have identified a t(8;9)(p21-23;p23-24) in seven male patients (mean age 50, range 32-74) with diverse hematologic malignancies and clinical outcomes: atypical chronic myeloid leukemia/chronic eosinophilic leukemia (n = 5), secondary acute myeloid leukemia (n = 1), and pre-B-cell acute lymphoblastic leukemia (n = 1). Initial fluorescence in situ hybridization studies of one patient indicated that the nonreceptor tyrosine kinase Janus-activated kinase 2 (JAK2) at 9p24 was disrupted. Rapid amplification of cDNA ends-PCR identified the 8p22 partner gene as human autoantigen pericentriolar material (PCM1), a gene encoding a large centrosomal protein with multiple coiled-coil domains. Reverse transcription-PCR and fluorescence in situ hybridization confirmed the fusion in this case and also identified PCM1–JAK2 in the six other t(8;9) patients. The breakpoints were variable in both genes, but in all cases the chimeric mRNA is predicted to encode a protein that retains several of the predicted coiled-coil domains from PCM1 and the entire tyrosine kinase domain of JAK2. Reciprocal JAK2–PCM1 mRNA was not detected in any patient. We conclude that human autoantigen pericentriolar material (PCM1)–JAK2 is a novel, recurrent fusion gene in hematologic malignancies. Patients with PCM1–JAK2 disease are attractive candidates for targeted signal transduction therapy.

263 citations

Journal ArticleDOI
TL;DR: Drug-induced cleavage of DNA by topoisomerase II mediates the formation of chromosomal translocation breakpoints in mitoxantrone-related APL and in APL that occurs after therapy with other topoisomersase II poisons.
Abstract: Background Chromosomal translocations leading to chimeric oncoproteins are important in leukemogenesis, but how they form is unclear. We studied acute promyelocytic leukemia (APL) with the t(15;17) translocation that developed after treatment of breast or laryngeal cancer with chemotherapeutic agents that poison topoisomerase II. Methods We used long-range polymerase chain reaction and sequence analysis to characterize t(15;17) genomic breakpoints in therapy-related APL. To determine whether topoisomerase II was directly involved in mediating breaks of double-stranded DNA at the observed translocation breakpoints, we used a functional in vitro assay to examine topoisomerase II–mediated cleavage in the normal homologues of the PML and RARA breakpoints. Results Translocation breakpoints in APL that developed after exposure to mitoxantrone, a topoisomerase II poison, were tightly clustered in an 8-bp region within PML intron 6. In functional assays, this “hot spot” and the corresponding RARA breakpoints were...

263 citations

Journal ArticleDOI
03 Oct 2013-Blood
TL;DR: Biology and prognosis in SM are related to the pattern of mutated genes that are acquired during disease evolution, and overall survival was significantly shorter in patients with additional aberrations as compared to those with KIT D816V only.

216 citations

Journal ArticleDOI
01 Jun 2007-Blood
TL;DR: Real-time quantitative-polymerase chain reaction assays are consistent with the exquisite sensitivity of the FIP1L1-PDGFRalpha fusion to imatinib, as compared with BCR-ABL, and underline the importance of RQ-PCR monitoring to guide management using molecularly targeted therapies.

186 citations


Cited by
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Journal ArticleDOI
30 Jul 2009-Blood
TL;DR: The classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.

4,274 citations

Journal ArticleDOI
TL;DR: These studies promise refined targeting of TOP2 as an effective anticancer strategy and the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy.
Abstract: Recent molecular studies have expanded the biological contexts in which topoisomerase II (TOP2) has crucial functions, including DNA replication, transcription and chromosome segregation. Although the biological functions of TOP2 are important for ensuring genomic integrity, the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy. The molecular tools that have allowed an understanding of the biological functions of TOP2 are also being applied to understanding the details of drug action. These studies promise refined targeting of TOP2 as an effective anticancer strategy.

1,466 citations

Journal ArticleDOI
01 Dec 2003-Leukemia
TL;DR: The development of standardized protocols for RQ-PCR analysis of FG transcripts provides a milestone for molecular determination of MRD levels and is likely to prove invaluable to the management of patients entered into multicenter therapeutic trials.
Abstract: Detection of minimal residual disease (MRD) has proven to provide independent prognostic information for treatment stratification in several types of leukemias such as childhood acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute promyelocytc leukemia. This report focuses on the accurate quantitative measurement of fusion gene (FG) transcripts as can be applied in 35-45% of ALL and acute myeloid leukemia, and in more than 90% of CML. A total of 26 European university laboratories from 10 countries have collaborated to establish a standardized protocol for TaqMan-based real-time quantitative PCR (RQ-PCR) analysis of the main leukemia-associated FGs within the Europe Against Cancer EAC) program. Four phases were scheduled: (1) training, (2) optimization, (3) sensitivity testing and (4) patient sample testing. During our program, three quality control rounds on a large series of coded RNA samples were performed including a balanced randomized assay, which enabled final validation of the EAC primer and probe sets. The expression level of the nine major FG transcripts in a large series of stored diagnostic leukemia samples (n = 278) was evaluated. After normalization, no statistically significant difference in expression level was observed between bone marrow and peripheral blood on paired samples at diagnosis. However, RQ-PCR revealed marked differences in FG expression between transcripts in leukemic samples at diagnosis that could account for differential assay sensitivity. The development of standardized protocols for RQ-PCR analysis of FG transcripts provides a milestone for molecular determination of MRD levels. This is likely to prove invaluable to the management of patients entered into multicenter therapeutic trials.

1,450 citations

Journal ArticleDOI
TL;DR: An analysis of available data shows that gene fusions occur in all malignancies, and that they account for 20% of human cancer morbidity, with the advent of new and powerful investigative tools that enable the detection of cytogenetically cryptic rearrangements.
Abstract: Chromosome aberrations, in particular translocations and their corresponding gene fusions, have an important role in the initial steps of tumorigenesis; at present, 358 gene fusions involving 337 different genes have been identified. An increasing number of gene fusions are being recognized as important diagnostic and prognostic parameters in malignant haematological disorders and childhood sarcomas. The biological and clinical impact of gene fusions in the more common solid tumour types has been less appreciated. However, an analysis of available data shows that gene fusions occur in all malignancies, and that they account for 20% of human cancer morbidity. With the advent of new and powerful investigative tools that enable the detection of cytogenetically cryptic rearrangements, this proportion is likely to increase substantially.

1,300 citations