Molecular prognostic factors and drug targets in acute leukemia

Die Identifikation molekularer Prognosefaktoren bei akuten Leukämien hat eine wichtige Bedeutung für die individuelle Risikoeinschätzung eines Patienten und stellt die Grundlage für die Entwicklung zielgerichteter Substanzen dar. Die Untersuchung molekularer Marker im Rahmen dieser Arbeit umfasst: 1. Prognostische Marker für eine bessere Risikostratifizierung von Patienten mit akuter lymphoblastischer Leukämie (BAALC und LEF1 Expression); 2. Prognostische und funktionelle Bedeutung von Regulatoren des Wnt- und Insulin- like growth factor (IGF) Signalweges in der akuten myeloischen Leukämie.Identification of molecular prognostic markers in acute leukemias is important to determine an individual patient’s risk and provides the basis for developing targeted therapies. Analyses of molecular markers presented here include: 1. prognostic markers for improved risk stratification of patients with acute lymphoblastic leukemia (BAALC and LEF1 expression); 2. prognostic and functional implications of regulators of the Wnt and IGF signaling pathways in acute myeloid leukemia

Mapping urban green – The capabilities of remote sensing data with spatial resolutions from 10 meters to 10 centimeters

Urban green plays a vital role in the urban ecosystem, providing benefits for society, ecology and economy. Particularly in cities, urban green infrastructure mitigates the urban heat island effect, promotes air quality and biodiversity, and provides spaces for recreation and leisure, among others. Despite these positive effects, detailed spatial information on urban green is still limited in many cities in Germany as well as worldwide. Against this background, remote sensing provides a cost-effective source of data for area-wide derivation of detailed information on green infrastructure in cities. This contribution aims at the presentation of different sources of remote sensing data with spatial resolutions from 10 meters to 10 centimeters for mapping urban green. In this work, we present an approach for land cover and vegetation classification based on free and open data from the Copernicus Sentinel-2 mission. In addition, we demonstrate capabilities of satellite based remote sensing with very-high spatial resolution (VHR) of less than one meter for urban green mapping. The derived information from VHR data can also be combined with imagery of coarser spatial resolution for vegetation fraction mapping using regression techniques. Finally, we showcase aerial imagery and a derived canopy height model with highest spatial resolution of 10 centimeters for detection and delineation of single trees in cities. Throughout, the presented approaches retrieved vital accuracies in the order of 80 to 90 % overall accuracy. While satellite-based imagery from the Sentinel-2 mission is available through a free, full and open data policy for the entire globe, the availability of VHR imagery is still limited due to data costs and spatial coverage. The use of aerial imagery is facilitated by municipal and federal administrations, who conduct regular acquisition of such data and enable its use at reasonable costs or make the data available free of charge. The wide range of remote sensing-based information on urban green not only facilitates the municipal management of green spaces, but also enables sustainable urban planning and informed decision-making in cities

R-GEM-Lenalidomide versus R-GEM-P as second-line treatment of diffuse large B-cell lymphoma: results of the UK NRCI phase II randomised LEGEND trial.

Outcome of patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) remains poor, highlighting the need for novel treatment approaches. The multicentre randomised phase II LEGEND trial evaluated lenalidomide in combination with rituximab, methylprednisolone and gemcitabine (R-GEM-L) vs. standard R-GEM-P as second-line treatment of DLBCL. The study closed early to recruitment after the planned interim analysis failed to demonstrate a complete response (CR) rate of ≥ 40% in either arm. Among 34 evaluable patients, 7/18 (38.9%) achieved CR with R-GEM-L and 3/16 (18.8%) with R-GEM-P. Median event-free and overall survival was 3.5/3.8 months and 10.8/8.3 months for R-GEM-L and R-GEM-P, respectively. The incidence of grade ≥ 3 toxicities was 52% in R-GEM-L and 83% in R-GEM-P. Efficacy and tolerability of R-GEM-L seem comparable with R-GEM-P and other standard salvage therapies, but a stringent design led to early trial closure. Combination of lenalidomide with gemcitabine-based regimens should be further evaluated in r/r DLBCL

Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia

The gene CXXC5 on 5q31 is frequently deleted in acute myeloid leukemia (AML) with del(5q), suggesting that inactivation of CXXC5 might play a role in leukemogenesis. Here, we investigated the functional and prognostic implications of CXXC5 expression in AML. CXXC5 mRNA was downregulated in AML with MLL rearrangements, t(8;21) and GATA2 mutations. As a mechanism of CXXC5 inactivation, we found evidence for epigenetic silencing by promoter methylation. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P = .007) and a better overall survival (OS, 46% vs 28%; P < .001) and event-free survival (EFS, 36% vs 21%; P < .001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene-expression profiling, lower CXXC5 expression was associated with upregulation of cell-cycling genes and codownregulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to affect the p53-dependent DNA damage response. In conclusion, our data suggest a tumor suppressor function of CXXC5 in AML. Inactivation of CXXC5 is associated with different leukemic pathways and defines an AML subgroup with better outcome

Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia

The gene CXXC5 on 5q31 is frequently deleted in acute myeloid leukemia (AML) with del(5q), suggesting that inactivation of CXXC5 might play a role in leukemogenesis. Here, we investigated the functional and prognostic implications of CXXC5 expression in AML.CXXC5 mRNA was downregulated in AML with MLL rearrangements, t(8;21) and GATA2 mutations. As a mechanism of CXXC5 inactivation, we found evidence for epigenetic silencing by promoter methylation. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P 5 .007) and a better overall survival (OS, 46% vs 28%; P < .001) and event-free survival (EFS, 36% vs 21%; P < .001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene-expression profiling, lower CXXC5 expression was associated with upregulation of cell-cycling genes and codownregulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to affect the p53-dependent DNA damage response. In conclusion, our data suggest a tumor suppressor function of CXXC5 in AML. Inactivation of CXXC5 is associated with different leukemic pathways and defines an AML subgroup with better outcome

Molecular markers in acute myeloid leukaemia

An increasing number of cytogenetic and molecular genetic aberrations have been identified in acute myeloid leukaemia (AML), highlighting the biological heterogeneity of the disease. Moreover, the characterisation of specific molecular abnormalities provides the basis for targeted therapies, such as all trans retinoic acid (ATRA) and arsenic trioxide treatment in acute promyelocytic leukaemia or tyrosine kinase inhibitors in AML with FLT3 mutations. Several cytogenetic and molecular genetic changes have been shown to be prognostically relevant and have been acknowledged in the latest WHO classification of AML as separate entities. A detailed marker assessment at diagnosis is crucial for risk-stratification of AML patients, allowing the identification of those at high risk of relapse, who may benefit from early allogeneic stem cell transplantation. Finally, molecular markers are important for the detection of minimal residual disease after initial therapy and during long-term follow-up, which enables a more tailored treatment approach for individual AML patients.</p