FLT3-ITD and TLR9 use Bruton tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation.

Acute myeloid leukemia (AML) is driven by niche-derived and cell-autonomous stimuli. Although many cell-autonomous disease drivers are known, niche-dependent signaling in the context of the genetic disease heterogeneity has been difficult to investigate. Here, we analyzed the role of Bruton tyrosine kinase (BTK) in AML. BTK was frequently expressed, and its inhibition strongly impaired the proliferation and survival of AML cells also in the presence of bone marrow stroma. By interactome analysis, (phospho)proteomics, and transcriptome sequencing, we characterized BTK signaling networks. We show that BTK-dependent signaling is highly context dependent. In Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive AML, BTK mediates FLT3-ITD-dependent Myc and STAT5 activation, and combined targeting of FLT3-ITD and BTK showed additive effects. In Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-negative AML, BTK couples Toll-like receptor 9 (TLR9) activation to nuclear factor κΒ and STAT5. Both BTK-dependent transcriptional programs were relevant for cell cycle progression and apoptosis regulation. Thus, we identify context-dependent oncogenic driver events that may guide subtype-specific treatment strategies and, for the first time, point to a role of TLR9 in AML. Clinical evaluation of BTK inhibitors in AML seems warranted.

The dual PI3K/mTOR inhibitor NVP-BGT226 induces cell cycle arrest and regulates Survivin gene expression in human pancreatic cancer cell lines.

The phosphatidylinositol-3-kinase (PI3K) pathway is one of the most commonly activated signaling pathways in pancreatic cancer and is a target of interest for new therapeutic approaches. NVP-BGT226 is a novel dual class PI3K/mammalian target of rapamycin (mTOR) inhibitor that has entered Phase I/II clinical trials. We analyzed the effect of NVP-BGT226 (10-100 nM) on the pancreatic cell lines Panc-1, BxPc-3, AsPC-1 and MiaPaCa-2 in regard to cell viability, induction of apoptosis, cell cycle, and expression of the antiapoptotic genes Survivin, MCL-1, BCL-2 and BCL-xL. Cell viability decreased within 24-72 h after exposure to about 50% compared to untreated control cells in a concentration- but not time-dependent manner. Cell cycle analysis revealed that NVP-BGT226 induced predominantly G0/G1 cell cycle arrest. Additionally, real-time RT-PCR and Western blot analysis showed a remarkable decrease of Survivin expression. Originally designed as a dual inhibitor, there was only a significant inhibition of p-mTOR. In summary, the dual PI3K/mTOR inhibitor NVP-BGT226 induces G0/G1 arrest and acts, at least, partially via downregulation of Survivin.

Simulation of equatorial and high-latitude jets on Jupiter in a deep convection model.

The bands of Jupiter represent a global system of powerful winds. Broad eastward equatorial jets are flanked by smaller-scale, higher-latitude jets flowing in alternating directions. Jupiter's large thermal emission suggests that the winds are powered from within, but the zonal flow depth is limited by increasing density and electrical conductivity in the molecular hydrogen-helium atmosphere towards the centre of the planet. Two types of planetary flow models have been explored: shallow-layer models reproduce multiple high-latitude jets, but not the equatorial flow system, and deep convection models only reproduce an eastward equatorial jet with two flanking neighbours. Here we present a numerical model of three-dimensional rotating convection in a relatively thin spherical shell that generates both types of jets. The simulated flow is turbulent and quasi-two-dimensional and, as observed for the jovian jets, simulated jet widths follow Rhines' scaling theory. Our findings imply that Jupiter's latitudinal transition in jet width corresponds to a separation between the bottom-bounded flow structures in higher latitudes and the deep equatorial flows.

Ionization and transport in partially ionized multicomponent plasmas: Application to atmospheres of hot Jupiters.

We study ionization and transport processes in partially ionized multicomponent plasmas. The plasma composition is calculated via a system of coupled mass-action laws. The electronic transport properties are determined by the electron-ion and electron-neutral transport cross sections. The influence of electron-electron scattering is considered via a correction factor to the electron-ion contribution. Based on these data, the electrical and thermal conductivities as well as the Lorenz number are calculated. For the thermal conductivity, we consider also the contributions of the translational motion of neutral particles and of the dissociation, ionization, and recombination reactions. We apply our approach to a partially ionized plasma composed of hydrogen, helium, and a small fraction of metals (Li, Na, Ca, Fe, K, Rb, and Cs) as typical for atmospheres of hot Jupiters. We present results for the plasma composition and the transport properties as a function of density and temperature and then along typical P-T profiles for the outer part of the hot Jupiter HD 209458b. The electrical conductivity profile allows revising the Ohmic heating power related to the fierce winds in the planet's atmosphere. We show that the higher temperatures suggested by recent interior models could boost the conductivity and thus the Ohmic heating power to values large enough to explain the observed inflation of HD 209458b.

Evidence from numerical experiments for a feedback dynamo generating Mercury's magnetic field.

The observed weakness of Mercury's magnetic field poses a long-standing puzzle to dynamo theory. Using numerical dynamo simulations, we show that it could be explained by a negative feedback between the magnetospheric and the internal magnetic fields. Without feedback, a small internal field was amplified by the dynamo process up to Earth-like values. With feedback, the field strength saturated at a much lower level, compatible with the observations at Mercury. The classical saturation mechanism via the Lorentz force was replaced by the external field impact. The resulting surface field was dominated by uneven harmonic components. This will allow the feedback model to be distinguished from other models once a more accurate field model is constructed from MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) and BepiColombo data.

Wilms' tumour gene 1 (WT1) as a target in curcumin treatment of pancreatic cancer cells.

The transcription factor WT1 plays an important role in cellular proliferation and survival of various cancer cells, and is frequently expressed in pancreatic cancer. Curcumin has been shown to be a potentially effective agent in pancreatic cancer. In this context, the purpose of this study was to determine the role of WT1 in a curcumin-treated pancreatic cancer cell line. To study the effect of curcumin on the expression of WT1, we incubated the pancreatic cancer cell line PANC-1 with different amounts of curcumin. The expression of WT1 on mRNA and protein level was measured with real-time RT-PCR and Western blot analysis. The incubation of the pancreatic cancer cell line PANC-1 with curcumin resulted in an inhibition of cellular proliferation as measured with MTT assay. The expression of WT1 on mRNA and protein level was significantly down-regulated in a concentration-dependent manner after treatment with curcumin. The WT1 mRNA levels were decreased by 20%, 25%, 40%, 78% and 88% in response to 10, 20, 30, 40 and 50 microM curcumin. The use of small inhibitory RNA (siRNA) targeting WT1 down-regulated the expression of WT1 about 90%. Combined treatment with curcumin and siRNA targeting WT1 resulted in a significant inhibition of cell proliferation compared to curcumin-treated cells alone. In conclusion, WT1 is involved in cellular proliferation of PANC-1 cells. Targeting WT1 gene expression with siRNA may enhance the efficacy of curcumin to inhibit cell proliferation.