Browsing by Subject "ACUTE MYELOID-LEUKEMIA"

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  • Kumar, Ashwini; Kankainen, Matti; Parsons, Alun; Kallioniemi, Olli; Mattila, Pirkko; Heckman, Caroline A. (2017)
    Background: RNA sequencing (RNA-seq) has become an indispensable tool to identify disease associated transcriptional profiles and determine the molecular underpinnings of diseases. However, the broad adaptation of the methodology into the clinic is still hampered by inconsistent results from different RNA-seq protocols and involves further evaluation of its analytical reliability using patient samples. Here, we applied two commonly used RNA-seq library preparation protocols to samples from acute leukemia patients to understand how poly-A-tailed mRNA selection (PA) and ribo-depletion (RD) based RNA-seq library preparation protocols affect gene fusion detection, variant calling, and gene expression profiling. Results: Overall, the protocols produced similar results with consistent outcomes. Nevertheless, the PA protocol was more efficient in quantifying expression of leukemia marker genes and showed better performance in the expression-based classification of leukemia. Independent qRT-PCR experiments verified that the PA protocol better represented total RNA compared to the RD protocol. In contrast, the RD protocol detected a higher number of non-coding RNA features and had better alignment efficiency. The RD protocol also recovered more known fusion-gene events, although variability was seen in fusion gene predictions. Conclusion: The overall findings provide a framework for the use of RNA-seq in a precision medicine setting with limited number of samples and suggest that selection of the library preparation protocol should be based on the objectives of the analysis.
  • Staquicini, D. I.; D'Angelo, S.; Ferrara, F.; Karjalainen, K.; Sharma, G.; Smith, T. L.; Tarleton, C. A.; Jaalouk, D. E.; Kuniyasu, A.; Baze, W. B.; Chaffee, B. K.; Hanley, P. W.; Barnhart, K. F.; Koivunen, E.; Marchio, S.; Sidman, R. L.; Cortes, J. E.; Kantarjian, H. M.; Arap, W.; Pasqualini, R. (2018)
    Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D (KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.
  • Scheid, C.; de Wreede, L.; van Biezen, A.; Koenecke, C.; Gohring, G.; Volin, L.; Maertens, J.; Finke, J.; Passweg, J.; Beelen, D.; Cornelissen, J. J.; Itälä-Remes, M.; Chevallier, P.; Russell, N.; Petersen, E.; Milpied, N.; Espiga, C. Richard; Peniket, A.; Sierra, J.; Mufti, G.; Crawley, C.; Veelken, J. H.; Ljungman, P.; Cahn, J. Y.; Alessandrino, E. P.; de Witte, T.; Robin, M.; Kroeger, N. (2017)
    The International Prognostic Scoring System has been revised (IPSS-R) to predict prognosis of patients with myelodysplastic syndromes at diagnosis. To validate the use of the IPSS-R assessed before transplant rather than at diagnosis we performed a retrospective analysis of the EBMT database. A total of 579 patients had sufficient information available to calculate IPSS-R at transplant. Median overall survival (OS) from transplant was significantly different according to IPSS-R: very low 23.6 months, low 55.0 months, intermediate 19.7 months, high 13.5 months, very high 7.8 months (P <0.001). In a multivariate Cox model the following parameters were significant risk factors for OS: IPSS-R, graft source, age and prior treatment. Median relapse free survival also showed significant differences according to IPSS-R: very low: 23.6 months, low: 24.8 months, intermediate 10.6 months, high 7.9 months, very high 5.5 months (P <0.001). Multivariate risk factors for relapse-free survival (RFS) were: IPSS-R, reduced intensity conditioning, graft source and prior treatment. A trend for an increased relapse incidence was noted for very high risk IPSS-R. We conclude that the IPSS-R at transplant is a useful prognostic score for predicting OS and RFS after transplantation, capturing both disease evolution and response to prior treatment before transplant.