Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.Peer reviewe

Insight into the shallow lithosphere structure and magmatic plumbing system beneath the Tristan da Cunha hot spot from geophysical and petrological studies

According to classical plume theory, the Tristan da Cunha plume is thought to have played a major role in the rifting of the South Atlantic margins and the creation of the aseismic Walvis Ridge by impinging at the base of the continental lithosphere shortly before or during the breakup of the South Atlantic margins. However, Tristan da Cunha is enigmatic as it cannot be clearly identified as a deep-rooted hot spot, but may instead be related to a more shallow feature in the mantle that could actually have been caused by the opening of the South Atlantic. The equivocal character of Tristan da Cunha is largely due to a lack of geophysical and petrological data in this region. We therefore staged a multi-disciplinary geophysical study of the region by acquiring passive marine electromagnetic and seismic data, and bathymetric data within the framework of the SPP1375 South Atlantic Margin Processes and Links with onshore Evolution (SAMPLE) funded by the German Science foundation. The experiment included two expeditions onboard the German R/V MARIA S. MERIAN in 2012 and 2013. In addition to the geophysical work, a landing party collected samples for petrological studies. In our contribution we present first results on the shallow lithosphere structure beneath the Tristan da Cunha archipelago derived from geophysical studies. These results are combined with results from thermobarometric analyses of basanitic/ankaramitic rocks that represent the main rock type on the island. The more evolved products of the eruption in 1962, (trachyandesites), were also studied to include the full range of magma compositions. Clinopyroxene-melt thermobarometry yielded crystallization pressures between 4 and 14 kbar, corresponding to depths of 12-42 km, whereby the youngest and most evolved rocks erupted from the shallowest depth. Olivine-, clinopyroxene-, and plagioclase-melt thermometry yielded magmatic temperatures of 1100° - 1320°C. The Moho below the archipelago is at approximately 11-12 km depth based on the receiver function method at two island stations and ocean-bottom seismometers. Therefore the petrologic depth estimates demonstrate that magmas erupted from a plumbing system in the uppermost mantle