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Haass W.,University of Heidelberg | Kleiner H.,University of Heidelberg | Weiss C.,University of Heidelberg | Haferlach C.,MLL Munchner Leukamielabor | And 6 more authors.
PLoS ONE | Year: 2015

Unbalanced (major route) additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukemia (CML) indicate an increased risk of progression and shorter survival. Moreover, newly arising ACA under imatinib treatment and clonal evolution are considered features of acceleration and define failure of therapy according to the European Leukemia-Net (ELN) recommendations. On the basis of 1151 Philadelphia chromosome positive chronic phase patients of the randomized CML-study IV, we examined the incidence of newly arising ACA under imatinib treatment with regard to the p210BCR-ABL breakpoint variants b2a2 and b3a2. We found a preferential acquisition of unbalanced ACA in patients with b3a2 vs. b2a2 fusion type (ratio: 6.3 vs. 1.6, p = 0.0246) concurring with a faster progress to blast crisis for b3a2 patients (p = 0.0124). ESPL1/Separase, a cysteine endopeptidase, is a key player in chromosomal segregation during mitosis. Separase overexpression and/or hyperactivity has been reported from a wide range of cancers and cause defective mitotic spindles, chromosome missegregation and aneuploidy. We investigated the influence of p210BCR-ABL breakpoint variants and imatinib treatment on expression and proteolytic activity of Separase as measured with a specific fluorogenic assay on CML cell lines (b2a2: KCL-22, BV-173; b3a2:K562, LAMA-84). Despite a drop in Separase protein levels an up to 5.4-fold increase of Separase activity under imatinib treatment was observed exclusively in b3a2 but not in b2a2 cell lines. Mimicking the influence of imatinib on BV-173 and LAMA-84 cells by ESPL1 silencing stimulated Separase proteolytic activity in both b3a2 and b2a2 cell lines. Our data suggest the existence of a fusion type-related feedback mechanism that posttranslationally stimulates Separase proteolytic activity after therapy-induced decreases in Separase protein levels. This could render b3a2 CML cells more prone to aneuploidy and clonal evolution than b2a2 progenitors and may therefore explain the cytogenetic results of CML patients. © 2015 Haaß et al.

Middeke J.M.,TU Dresden | Beelen D.,Universitatsklinikum Essen | Stadler M.,Klinik fur Hamatologie | Gohring G.,Institute For Zell Und Molekularpathologie | And 12 more authors.
Blood | Year: 2012

The European LeukemiaNet classification combines a heterogeneous group of aberrations as adverse-risk abnormalities. Our goal was to investigate the outcomes associated with distinct high-risk chromosomal abnormalities in acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). We performed a retrospective cohort analysis in patients with high-risk AML who received first, HLA-compatible, allogeneic HSCT between January 2005 and December 2008. Data from 236 patients with a median age of 55 years were included. Because complex karyotype (CK), -5/5q-, and abnl(17p) are overlapping categories, a hierarchical classification system based on the presence or absence of abnl(17p) and -5/5q- was developed. Patients with abnl(17p) had a 2-year event-free survival (EFS) of 11%(95% confidence interval [CI], 0%-25%), patients with -5/5q- but no abnl(17p) a 2-year EFS of 29% (95% CI, 14%-44%), and patients with adverse-riskAMLbut neither of the 2 marker lesions a 2-year EFS of 49% (95% CI, 39%- 59%). Notably, complex and monosomal karyotypes lost their prognostic value when these marker lesions were excluded. In conclusion, hierarchical classification of adverse-risk karyotypes by 2 marker lesions, abnl(17p) and -5/5q-, is effective in prognostication of the outcome of allogeneic HSCT in AML. © 2012 by The American Society of Hematology.

Moog U.,University of Heidelberg | Bierhals T.,University of Hamburg | Brand K.,University of Hamburg | Bautsch J.,University of Hamburg | And 14 more authors.
Orphanet Journal of Rare Diseases | Year: 2015

Background: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. Methods: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. Results: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. Conclusions: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) syndromic/nonsyndromic mild to severe ID with or without nystagmus caused by CASK missense and splice mutations that leave the CASK protein intact but likely alter its function or reduce the amount of normal protein. Our findings facilitate focused testing of the CASK gene and interpreting sequence variants identified by next-generation sequencing in cases with a phenotype resembling either of the three groups. © 2015 Moog et al.; licensee BioMed Central.

Leutloff S.,Institute For Zell Und Molekularpathologie | Holtkamp U.,Deutsche Leukamie and Lymphom Hilfe e.V. | Schlegelberger B.,Institute For Zell Und Molekularpathologie
Onkologe | Year: 2012

When young patients have overcome cancer, the question often arises whether they can still have children and whether, due to previous chemotherapy or radiation therapy, an increased risk of malformation for their children exists. In particular, if a pregnancy occurs during cancer illness or ongoing therapy, there is the fear that the child may have been damaged by the treatment. Not least, parents fear that the cancer might reoccur in their own children. Above all, if there is a question of risk of recurrence, a detailed family history is necessary and genetic counseling should be offered to determine whether the cancer incidence could have a genetic cause. Parents and children should be treated in specialized clinics and supervised by an interdisciplinary team. © Springer-Verlag 2012.

Ripperger T.,Institute For Zell Und Molekularpathologie | Schlegelberger B.,Institute For Zell Und Molekularpathologie | Steinemann D.,Institute For Zell Und Molekularpathologie
Medizinische Genetik | Year: 2012

Juvenile myelomonocytic leukemia (JMML) is a unique myeloproliferative disorder of early childhood in which mutations in NRAS, KRAS, PTPN11, NF1 and CBL are frequently found. Using high-resolution oligo array-based comparative genomic hybridization (aCGH), 20 JMML samples were investigated for submicroscopic genomic copy number alterations. Besides known cytogenetic aberrations, ten samples displayed additional submicroscopic alterations. Interestingly, an almost identical gain of chromosome 8 was identified in two patients. Subsequently, fluorescence in situ hybridization indicated a constitutional partial trisomy 8 mosaic (cT8M) in both patients. A survey on 27 cT8M patients with reported malignancies showed a predominance of myeloid malignancies including JMML. Our results dramatically reduce the critical region on chromosome 8 to 8p11.21q11.21. To determine how constitutional partial trisomy 8 mosaicisms may contribute to leukemogenesis in different mutational subtypes of JMML and other myeloid malignancies, further investigations are required. © 2012 Springer-Verlag.

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