Clonal evolution including partial loss of human leukocyte antigen genes favoring extramedullary acute myeloid leukemia relapse after matched related allogeneic hematopoietic stem cell transplantation
Stolzel F.,Universitatsklinikum Carl Gustav Carus |
Hackmann K.,Carl Gustav Carus Institute |
Kuithan F.,Carl Gustav Carus Institute |
Mohr B.,Universitatsklinikum Carl Gustav Carus |
And 15 more authors.
Background. Relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) leaves few therapeutic options, and mechanisms of immune escape of recurring leukemic cells remain poorly understood. Recently, acquired loss of mismatched human leukocyte antigen (HLA) was demonstrated in patients with AML undergoing haploidentical allogeneic HSCT and was suggested not to occur in HLA-matched HSCT. We hypothesized that this mechanism applies to extramedullary AML relapse which occurs frequently after allogeneic HSCT and might also not be restricted to haploidentical HSCT. Methods. DNA from extramedullary AML relapse after HSCT was compared with bone marrow at diagnosis with array comparative genomic hybridization to investigate relapse-specific genomic aberrations in relapsing AML after allogeneic HSCT. Formalin-fixed, paraffin-embedded tissues from the same points of time were assessed for HLA, major histocompatibility complex class I chain-related gene A, and TAP2 immunohistochemistry staining to assess cell surface expression of deleted loci encoded on chromosome 6p. Results. Array comparative genomic hybridization revealed a partial loss of chromosome 6p in extramedullary myeloid sarcoma relapse of AML after sustained complete remission was achieved through matched related allogeneic HSCT. Among others, a deleted region 6p21.32-p21.33, which included several HLA class I genes, was detected. Conclusions. These results suggest that the loss of HLA class I haplotype also occurs in AML relapse after HLA-matched related HSCT. Partial loss of several HLA class I genes and subsequent reduced presentation of minor histocompatibility antigens and reduced ligation of activating natural killer-cell receptors may explain the loss of graft-versus-leukemia response and extramedullary AML relapse in tissue with reduced immunologic surveillance. © 2012 by Lippincott Williams & Wilkins. Source
Topfer K.,TU Dresden |
Cartellieri M.,Helmholtz Center Dresden |
Michen S.,TU Dresden |
Wiedemuth R.,TU Dresden |
And 6 more authors.
Journal of Immunology
NK cells are emerging as new effectors for immunotherapy of cancer. In particular, the genetic engraftment of chimeric Ag receptors (CARs) in NK cells is a promising strategy to redirect NK cells to otherwise NK cell-resistant tumor cells. On the basis of DNAX-activation protein 12 (DAP12), a signaling adaptor molecule involved in signal transduction of activating NK cell receptors, we generated a new type of CAR targeting the prostate stem cell Ag (PSCA). We demonstrate in this article that this CAR, designated anti-PSCA-DAP12, consisting of DAP12 fused to the anti-PSCA single-chain Ab fragment scFv(AM1) confers improved cytotoxicity to the NK cell line YTS against PSCA-positive tumor cells when compared with a CAR containing the CD3ζ signaling chain. Further analyses revealed phosphorylation of the DAP12-associated ZAP-70 kinase and IFN-γ release of CAR-engineered cells after contact with PSCA-positive target cells. YTS cells modified with DAP12 alone or with a CAR bearing a phosphorylation-defective ITAM were not activated. Notably, infused YTS cells armed with anti-PSCA-DAP12 caused delayed tumor xenograft growth and resulted in complete tumor eradication in a significant fraction of treated mice. The feasibility of the DAP12-based CAR was further tested in human primary NK cells and confers specific cytotoxicity against KIR/HLA-matched PSCA-positive tumor cells, which was further enhanced by KIR-HLA mismatches. We conclude that NK cells engineered with DAP12-based CARs are a promising tool for adoptive tumor immunotherapy. Copyright © 2015 by The American Association of Immunologists, Inc. Source
Abdul-Aziz M.A.,Leibniz Institute for Natural Product Research and Infection Biology |
Abdul-Aziz M.A.,Friedrich - Schiller University of Jena |
Schofl G.,Leibniz Institute for Natural Product Research and Infection Biology |
Schofl G.,DKMS Life Science Laboratory GmbH |
And 5 more authors.
Ecology and Evolution
Here we used both microsatellites and mtCR (mitochondrial DNA control region) sequences as genetic markers to examine the genetic diversity and population structure of Penaeus monodon shrimp from six Indonesian regions. The microsatellite data showed that shrimp from the Indian and the Pacific Ocean were genetically distinct from each other. It has been reported previously that P. monodon mtCR sequences from the Indo-Pacific group into two major paralogous clades of unclear origin. Here we show that the population structure inferred from mtCR sequences matches the microsatellite-based population structure for one of these clades. This is consistent with the notion that this mtCR clade shares evolutionary history with nuclear DNA and may thus represent nuclear mitochondrial pseudogenes (Numts). While examining genetic diversity and population structure of Penaeus monodon shrimp in Indonesian waters. Similarities between mtCR sequences and microsatellite data for one mtCR clade are discovered. Evidence points towards nuclear DNA as source of this mtCR clade. © 2015 Published by John Wiley & Sons Ltd. Source
Chainonthee W.,TU Dresden |
Bornhauser M.,TU Dresden |
Fussel M.,DKMS Life Science Laboratory GmbH |
Ehninger G.,TU Dresden |
And 2 more authors.
Open Cancer Immunology Journal
In this retrospective study, the influence of donor and recipient KIR-gene content and their respective ligands including clinical parameters as potential confounding variables on the outcome of 150 acute myeloid leukemia (AML) patients undergoing allogenic hematopoietic cell transplantation (HCT) from unrelated donors was systematically investigated. There was no significant influence of KIR ligand mismatching and of donor/recipient KIR haplotype combinations on overall survival (OS), disease free survival (DSF), non-relapse mortality (NRM) and relapse. Isolated effects of KIR haplotypes, were detected for acute, chronic Graft versus Host Disease (aGvHD and cGvHD) as well as for the cumulative incidence of non-relapse mortality and relapse. The incidence of non-relapse mortality was evaluated in donor and recipient pairs harbouring KIR AA homozygosity (AA/Bx: p=0.038, HR=0.73, 95% CI=0.35-1.46 and AA/AA: p=0.043, HR=0.64, 95% CI 0.53-1-17). Our data suggest that KIR genotyping may be useful in patients in whom several HLAidentical unrelated donors can be identified but is probably not necessary for the primary donor selection algorithm. © Chainonthee et al.; Licensee Bentham Open. Source
Maiwald S.,TU Dresden |
Wehner R.,TU Dresden |
Schmitz M.,TU Dresden |
Schmitz M.,Center for Regenerative Therapies |
And 6 more authors.
Immunomodulatory properties of IDO1 relate to tryptophan catabolism. The degradation of tryptophan by IDO1 leads to suppression of T cell responses. Recently, another enzyme with IDO-like activity, indoleamine 2,3-dioxygenase-like-protein 1 (INDOL1, IDO2), has been described in both mice and humans.In order to study the gene expression of IDO1 and IDO2, we have developed a quantitative PCR (qPCR) assay. In an exploratory application to the study of the differential expression of IDO1 and IDO2 by professional antigen-presenting cells and MSCs (mesenchymal stromal cells) under the influence of interferon-γ (IFN-γ) and T-lymphocyte conditioned media (TCM), substantial differences were observed. IDO expression measured by qPCR was valid and reliable in the cell types investigated. Further studies are needed to delineate factors driving IDO expression in MSCs. © 2010 John Wiley & Sons A/S. Source