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Willasch A.M.,Goethe University Frankfurt | Kreyenberg H.,Goethe University Frankfurt | Shayegi N.,Universitatsklinikum Carl Gustav Carus der Technischen University | Rettinger E.,Goethe University Frankfurt | And 11 more authors.
Biology of Blood and Marrow Transplantation | Year: 2014

Quantitative real-time PCR (qPCR) has been proposed as a highly sensitive method for monitoring hematopoietic chimerism and may serve as a surrogate marker for the detection of minimal residual disease minimal residual disease in myelodysplastic syndrome (MDS), until specific methods of detection become available. Because a systematic comparison of the clinical utility of qPCR with the gold standard short tandem repeat (STR)-PCR has not been reported, we retrospectively measured chimerism by qPCR in 54 children transplanted for MDS in a previous study. Results obtained by STR-PCR in the initial study served as comparison. Because the detection limit of qPCR was sufficiently low to detect an autologous background, we defined the sample as mixed chimera if the proportion of recipient-derived cells exceeded .5%. The true positive rates were 100% versus 80% (qPCR versus STR-PCR, not significant), and mixed chimerism in most cases was detected earlier by qPCR than by STR-PCR (median, 31days) when chimerism was quantified concurrently in peripheral blood and bone marrow. Both methods revealed a substantial rate of false positives (22.7% versus 13.6%, not significant), indicating the importance of serial testing of chimerism to monitor its progression. Finally, we propose criteria for monitoring chimerism in pediatric MDS with regard to the subtypes, specimens, PCR method, and timing of sampling. © 2014 American Society for Blood and Marrow Transplantation. Source

Shayegi N.,Universitatsklinikum Carl Gustav Carus der Technischen University | Meyer C.,Universitatsklinikum Carl Gustav Carus der Technischen University | Lambert K.,Universitatsklinikum Carl Gustav Carus der Technischen University | Ehninger G.,Universitatsklinikum Carl Gustav Carus der Technischen University | And 2 more authors.
British Journal of Haematology | Year: 2014

Both immunosuppressive and cytoreductive effects of γ-irradiation contribute to engraftment of allogeneic haematopoietic stem and progenitor cells. We hypothesized that a release of host stem and progenitor cells from the niche prior to conditioning would permit engraftment after less intensive conditioning. Administration of AMD3100 and SEW2871 on days -4 to -2 followed by irradiation on day -1 in a non-myeloablative zebrafish transplant model resulted in a reduced radiation minimum dose of 10 Gy from 15 Gy being sufficient for engraftment. Targeting the SDF-1 (CXCL12)/CXCR4- and S1P/S1P1-axis increased the efficacy of allografting in an experimental transplant model. © 2013 John Wiley & Sons Ltd. Source

Wermke M.,Universitatsklinikum Carl Gustav Carus der Technischen University | Wermke M.,Medizinische Fakultat der Technischen University | Camgoz A.,Medizinische Fakultat der Technischen University | Paszkowski-Rogacz M.,Medizinische Fakultat der Technischen University | And 11 more authors.
Blood | Year: 2015

Acute myeloid leukemia (AML) is characterized by a marked genetic heterogeneity, which complicates the development of novel therapeutics. The delineation of pathways essential within an individual patient's mutational background might overcome this limitation and facilitate personalized treatment. We report the results of a large-scale lentiviral lossof-function RNA interference (RNAi) screen in primary leukemic cells. Stringent validation identified 6 genes (BNIPL1, ROCK1, RPS13, STK3, SNX27, WDHD1) whose knockdown impaired growth and viability of the cells. Dependence on these genes was not caused by mutation or overexpression, and although some of the candidates seemed to be rather patient specific, others were essential in cells isolated from other AML patients. In addition to the phenotype observed after ROCK1 knockdown, treatment with the approved ROCK inhibitor fasudil resulted in increased apoptosis and decreased viability of primary AML cells. In contrast to observations in some other malignancies, ROCK1 inhibition did not foster growth of immature malignant progenitors but was toxic to this cell fraction in feeder coculture and xenotransplant experiments, indicating a distinct effect of ROCK1 inhibition on leukemic progenitors. We conclude that large-scale RNAi screens in primary patient-derived cells are feasible and can complement other methods for personalized cancer therapies, such as expression and mutation profiling. © 2015 by The American Society of Hematology. Source

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