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- Giagounidis, Aristoteles, et al.
(författare)
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Outcomes in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with isolated deletion 5q treated with lenalidomide: a subset analysis from the MDS-004 study
- 2014
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 93:5, s. 429-438
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveA subset analysis of the randomised, phase 3, MDS-004 study to evaluate outcomes in patients with International Prognostic Scoring System (IPSS)-defined Low-/Intermediate (Int)-1-risk myelodysplastic syndromes (MDS) with isolated del(5q). MethodsPatients received lenalidomide 10mg/d (days 1-21; n=47) or 5mg/d (days 1-28; n=43) on 28-d cycles or placebo (n=45). From the placebo and lenalidomide 5mg groups, 84% and 58% of patients, respectively, crossed over to lenalidomide 5 or 10mg at 16wk, respectively. ResultsRates of red blood cell-transfusion independence (RBC-TI) 182d were higher in the lenalidomide 10mg (57.4%; P<0.0001) and 5mg (37.2%; P=0.0001) groups vs. placebo (2.2%). Cytogenetic response rates (major+minor responses) were 56.8% (P<0.0001), 23.1% (P=0.0299) and 0%, respectively. Two-year cumulative risk of acute myeloid leukaemia progression was 12.6%, 17.4% and 16.7% in the lenalidomide 10mg, 5mg, and placebo groups, respectively. In a 6-month landmark analysis, overall survival was longer in lenalidomide-treated patients with RBC-TI 182d vs. non-responders (P=0.0072). The most common grade 3-4 adverse event was myelosuppression. ConclusionsThese data support the clinical benefits and acceptable safety profile of lenalidomide in transfusion-dependent patients with IPSS-defined Low-/Int-1-risk MDS with isolated del(5q).
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| 2. |
- Reimer, Jana, et al.
(författare)
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CRISPR-Cas9-induced t(11;19)/MLL-ENL translocations initiate leukemia in human hematopoietic progenitor cells in vivo
- 2017
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 102:9, s. 1558-1566
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Tidskriftsartikel (refereegranskat)abstract
- Chromosomal translocations that generate oncogenic fusion proteins are causative for most pediatric leukemias and frequently affect the MLL/ KMT2A gene. In vivo modeling of bona fide chromosomal translocations in human hematopoietic stem and progenitor cells is challenging but essential to determine their actual leukemogenic potential. We therefore developed an advanced lentiviral CRISPR-Cas9 vector that efficiently transduced human CD34(+) hematopoietic stem and progenitor cells and induced the t(11; 19)/MLL-ENL translocation. Leveraging this system, we could demonstrate that hematopoietic stem and progenitor cells harboring the translocation showed only a transient clonal growth advantage in vitro. In contrast, t(11; 19)/MLL-ENL-harboring CD34(+) hematopoietic stem and progenitor cells not only showed longterm engraftment in primary immunodeficient recipients, but t(11; 19)/ MLL-ENL also served as a first hit to initiate a monocytic leukemia-like disease. Interestingly, secondary recipients developed acute lymphoblastic leukemia with incomplete penetrance. These findings indicate that environmental cues not only contribute to the disease phenotype, but also to t(11; 19)/ MLL-ENL-mediated oncogenic transformation itself. Thus, by investigating the true chromosomal t(11; 19) rearrangement in its natural genomic context, our study emphasizes the importance of environmental cues for the pathogenesis of pediatric leukemias, opening an avenue for novel treatment options.
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| 3. |
- Wessels, Kathrin, et al.
(författare)
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Novel CHD7 mutations contributing to the mutation spectrum in patients with CHARGE syndrome
- 2010
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Ingår i: EUROPEAN JOURNAL OF MEDICAL GENETICS. - : Elsevier Science B.V., Amsterdam. - 1769-7212. ; 53:5, s. 280-285
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Tidskriftsartikel (refereegranskat)abstract
- CHARGE syndrome is an autosomal dominant inherited multiple malformation disorder typically characterized by coloboma, choanal atresia, hypoplastic semicircular canal, cranial nerve defects, cardiovascular malformations and ear abnormalities. Mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene are the major cause of CHARGE syndrome. Mutation analysis was performed in 18 patients with firm or tentative clinical diagnosis of CHARGE syndrome. In this study eight mutations distributed across the gene were found. Five novel mutations - one missense (c.2936Tandgt;C), one nonsense (c.8093Candgt;A) and three frameshift mutations (c.804_805insAT, c.1757_1770del14, c.1793delA) - were identified. As far as familial data were available these mutations were found to have arisen de novo. Comparison of the clinical features of patients with the same mutation demonstrates that expression of the phenotype is highly variable. The mutation detection rate in this study was 44.4% in patients with a clinically established or suspected diagnosis of CHARGE syndrome.
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