Carolin Walter

Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications

Mutations in the cohesin complex are novel, genetic lesions in acute myeloid leukemia (AML) that are not well characterized. In this study, we analyzed the frequency, clinical, and prognostic implications of mutations in STAG1, STAG2, SMC1A, SMC3, and RAD21, all members of the cohesin complex, in a cohort of 389 uniformly treated AML patients by next generation sequencing. We identified a total of 23 patients (5.9%) with somatic mutations in 1 of the cohesin genes. All gene mutations were mutually exclusive, and STAG1 (1.8%), STAG2 (1.3%), and SMC3 (1.3%) were most frequently mutated. Patients with any cohesin complex mutation had lower BAALC expression levels. We found a strong association between mutations affecting the cohesin complex and NPM1. Mutated allele frequencies were similar between NPM1 and cohesin gene mutations. Overall survival (OS), relapse-free survival (RFS), and complete remission rates (CR) were not influenced by the presence of cohesin mutations (OS: hazard ratio [HR] 0.98; 95% confidence interval [CI], 0.56-1.72 [P = .94]; RFS: HR 0.7; 95% CI, 0.36-1.38 [P = .3]; CR: mutated 83% vs wild-type 76% [P = .45]). The cohesin complex presents a novel pathway affected by recurrent mutations in AML. This study is registered at www.clinicaltrials.gov as #NCT00209833.

Genetic characterization of acquired aplastic anemia by targeted sequencing.

Aplastic anemia (AA) is a rare but life-threatening bone marrow failure syndrome; diagnosis is based on cytopenias in peripheral blood and hypocellularity in bone marrow. The distinction between AA and hypocellular myelodysplastic syndrome (MDS) is often difficult to verify, and AA evolves into MDS

Basic4Cseq: an R/Bioconductor package for analyzing 4C-seq data

SUMMARY Basic4Cseq is an R/Bioconductor package for basic filtering, analysis and subsequent near-cis visualization of 4C-seq data. The package processes aligned 4C-seq raw data stored in binary alignment/map (BAM) format and maps the short reads to a corresponding virtual fragment library. Functions are included to create virtual fragment libraries providing chromosome position and further information on 4C-seq fragments (length and uniqueness of the fragment ends, and blindness of a fragment) for any BSGenome package. An optional filter is included for BAM files to remove invalid 4C-seq reads, and further filter functions are offered for 4C-seq fragments. Additionally, basic quality controls based on the read distribution are included. Fragment data in the vicinity of the experiments viewpoint are visualized as coverage plot based on a running median approach and a multi-scale contact profile. Wig files or csv files of the fragment data can be exported for further analyses and visualizations of interactions with other programs. AVAILABILITY AND IMPLEMENTATION Basic4Cseq is implemented in R and available at http://www.bioconductor.org/. A vignette with detailed descriptions of the functions is included in the package. CONTACT Carolin.Walter@uni-muenster.de SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

Myeloid leukemia with transdifferentiation plasticity developing from T-cell progenitors

Unfavorable patient survival coincides with lineage plasticity observed in human acute leukemias. These cases are assumed to arise from hematopoietic stem cells, which have stable multipotent differentiation potential. However, here we report that plasticity in leukemia can result from instable lineage identity states inherited from differentiating progenitor cells. Using mice with enhanced c‐Myc expression, we show, at the single‐cell level, that T‐lymphoid progenitors retain broad malignant lineage potential with a high capacity to differentiate into myeloid leukemia. These T‐cell‐derived myeloid blasts retain expression of a defined set of T‐cell transcription factors, creating a lymphoid epigenetic memory that confers growth and propagates myeloid/T‐lymphoid plasticity. Based on these characteristics, we identified a correlating human leukemia cohort and revealed targeting of Jak2/Stat3 signaling as a therapeutic possibility. Collectively, our study suggests the thymus as a source for myeloid leukemia and proposes leukemic plasticity as a driving mechanism. Moreover, our results reveal a pathway‐directed therapy option against thymus‐derived myeloid leukemogenesis and propose a model in which dynamic progenitor differentiation states shape unique neoplastic identities and therapy responses.

Lmo2 expression defines tumor cell identity during T‐cell leukemogenesis

The impact of LMO2 expression on cell lineage decisions during T‐cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T‐cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human‐like T‐ALL. In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T‐ALL. The resulting T‐ALLs lacked LMO2 and its target‐gene expression, and histologically, transcriptionally, and genetically similar to human LMO2‐driven T‐ALL. We next found that during T‐ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T‐ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre‐mediated activation of Lmo2 at different stages of B‐cell development induces systematically and unexpectedly T‐ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T‐ALL to current therapies.

Evaluation of field of view calibration techniques for head-mounted displays

In this poster we present a comparison of two calibration techniques that allow to determine the field of view (FOV) for immersive head-mounted displays (HMDs).