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München, Germany

Turkmen S.,Labor Berlin | Turkmen S.,Charite - Medical University of Berlin | Timmermann B.,Max Planck Institute For Molekulare Genetik | Bartels G.,Charite - Medical University of Berlin | And 9 more authors.
Genes Chromosomes and Cancer | Year: 2012

While the MLL "recombinome" is relatively well characterized in B-cell precursor acute lymphoblastic leukemia (BCP ALL), available data for adult acute T-lymphoblastic leukemia (T-ALL) are scarce. We performed fluorescence in situ hybridization (FISH) for an MLL split signal on 223 adult T-ALL samples obtained within the framework of the German Multicenter ALL 07/2003 therapy trial. Three biphenotypic leukemias (T-ALL/AML) were also included in the analysis. Samples showing any alteration by FISH were further investigated to characterize the MLL aberration. In addition, they were investigated for common genetic lesions known in T-ALL. Twenty-two cases (9.5%) showed an abnormal MLL signal by FISH analysis. Most of these appeared to be deletions or gains but in five cases (2.1%) a chromosomal translocation involving the MLL gene was identified. The translocation partners and chromosomal breakpoints were molecularly characterized. Three T-ALLs had an MLL-AF6/t(6;11) and two biphenotypic leukemias had an MLL-ELL/t(11;19). The chromosomal breakpoints in two of the MLL-AF6-positive cases were located outside the classical MLL major breakpoint cluster known from BCP ALL. In conclusion, the spectrum of MLL translocation partners in adult T-ALL much more resembles that of AML than that of BCP ALL and thus the mechanisms by which MLL contributes to leukemogenesis in adult T-ALL appear to differ from those in BCP ALL. Proposals are made for the diagnostic assessment of MLL fusion genes in adult T-ALL. © 2012 Wiley Periodicals, Inc. Source


Heesch S.,Charite - Medical University of Berlin | Heesch S.,Free University of Berlin | Schlee C.,Charite - Medical University of Berlin | Neumann M.,Charite - Medical University of Berlin | And 9 more authors.
Leukemia | Year: 2010

Over expression of BAALC (brain and acute leukemia, cytoplasmic) predicts an inferior outcome in acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients. To identify BAALC-associated genes that give insights into its functional role in chemotherapy resistance, gene expression signatures differentiating high from low BAALC expressers were generated from normal CD34 progenitors, T-acute lymphoblastic leukemia (T-ALL) and AML samples. The insulin-like growth factor binding protein 7 (IGFBP7) was one of the four genes (CD34, CD133, natriuretic peptide receptor C (NPR3), IGFBP7) coexpressed with BAALC and common to the three entities. In T-ALL, high IGFBP7-expression was associated with an immature phenotype of early T-ALL (P0.001), expression of CD34 (P0.001) and CD33 (P0.001). Moreover, high IGFBP7-expression predicted primary therapy resistance (P0.03) and inferior survival in T-ALL (P0.03). In vitro studies revealed that IGFBP7 protein significantly inhibited the proliferation of leukemia cell lines (Jurkat cells: 42% reduction, P0.002; KG1a cells: 65% reduction, P0.001). In conclusion, IGFBP7 was identified as a BAALC coexpressed gene. Furthermore, high IGFBP7 was associated with stem cell features and treatment failure in T-ALL. In contrast to BAALC, which likely represents only a surrogate marker of treatment failure in acute leukemia, IGFBP7 regulates the proliferation of leukemic cells and might be involved in chemotherapy resistance. © 2010 Macmillan Publishers Limited All rights reserved. Source


Kuhnl A.,Charite - Medical University of Berlin | Gokbuget N.,Goethe University Frankfurt | Stroux A.,Charite - Medical University of Berlin | Burmeister T.,Charite - Medical University of Berlin | And 7 more authors.
Blood | Year: 2010

Overexpression of BAALC is an adverse prognostic factor in adults with cytogenetically normal acute myeloid leukemia and T-cell acute lymphoblastic leukemia (ALL). Here, we analyzed the prognostic significance of BAALC in B-precursor ALL. BAALC MRNA expression was determined in 368 primary adult B-precursor ALL patients enrolled on the 06/99 and 07/03 GMALL trials. Patients were grouped into tertiles according to BAALC expression (T1-T3). Higher BAALC expression (T3 vs T2 vs T1) was associated with higher age (P < .001), a higher white blood cell count (P = .008), CD34 (P = .001), BCR-ABL (P < .001), and MLL-AF4 (P < .001). Higher BAALC expression predicted primary therapy resistance in the overall cohort (P = .002) and in the BCR-ABL - and MLL-AF4- subgroup (P = .01). In BCR-ABL- and MLL-AF4- patients, higher BAALC expression was associated with a shorter overall survival (OS; 5-year OS: T3, 38%; T2, 52%; T1, 70%; P = .004) and independently predicted OS in multivariate models (P = .03). Gene-expression profiling revealed an upregulation of stem cell markers and genes involved in chemoresistance (TSPAN7 and LYN) in the high BAALC group. Thus, high BAALC expression is associated with an immature, chemoresistant leukemic phenotype and identifies patients with inferior OS. Determination of BAALC might contribute to risk assessment of molecularly undefined adult B-precursor ALL. © 2010 by The American Society of Hematology. Source


Schmidt M.,Universitatsklinikum Jena | Rinke J.,Universitatsklinikum Jena | Schafer V.,Universitatsklinikum Jena | Schnittger S.,MLL Munchner Leukamie Labor | And 10 more authors.
Leukemia | Year: 2014

To study clonal evolution in chronic myeloid leukemia (CML), we searched for BCR-ABL-independent gene mutations in both Philadelphia chromosome (Ph)-negative and Ph-positive clones in 29 chronic-phase CML patients by targeted deep sequencing of 25 genes frequently mutated in myeloid disorders. Ph-negative clones were analyzed in 14 patients who developed clonal cytogenetic abnormalities in Ph-negative cells during treatment with tyrosine kinase inhibitors (TKI). Mutations were detected in 6/14 patients (43%) affecting the genes DNMT3A, EZH2, RUNX1, TET2, TP53, U2AF1 and ZRSR2. In two patients, the mutations were also found in corresponding Ph-positive diagnostic samples. To further investigate Ph-positive clones, 15 randomly selected CML patients at diagnosis were analyzed. Somatic mutations additional to BCR-ABL were found in 5/15 patients (33%) affecting ASXL1, DNMT3A, RUNX1 and TET2. Analysis of individual hematopoietic colonies at diagnosis revealed that most mutations were part of the Ph-positive clone. In contrast, deep sequencing of subsequent samples during TKI treatment revealed one DNMT3A mutation in Ph-negative cells that was also present in Ph-positive cells at diagnosis, implying that the mutation preceded the BCR-ABL rearrangement. In summary, BCR-ABL-independent gene mutations were frequently found in Ph-negative and Ph-positive clones of CML patients and may be considered as important cofactors in the clonal evolution of CML. © 2014 Macmillan Publishers Limited. All rights reserved. Source

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