Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins.

Internal tandem duplications in the FMS-like tyrosine kinase-3 (FLT3-ITD) are common mutations in acute myeloid leukemia (AML). Proteolysis-targeting chimeras (PROTACs) that induce proteasomal degradation of mutated FLT3 emerge as innovative pharmacological approach. Molecular mechanisms that control targeted proteolysis beyond the ubiquitin-proteasome-system are undefined and PROTACs are the only known type of FLT3 degraders. We report that the von-Hippel-Lindau ubiquitin-ligase based FLT3 PROTAC MA49 (melotinib-49) and the FLT3 hydrophobic tagging molecule MA50 (halotinib-50) reduce endoplasmic reticulum-associated, oncogenic FLT3-ITD but spare FLT3. Nanomolar doses of MA49 and MA50 induce apoptosis of human leukemic cell lines and primary AML blasts with FLT3-ITD (p < 0.05-0.0001), but not of primary hematopoietic stem cells and differentiated immune cells, FLT3 wild-type cells, retinal cells, and c-KIT-dependent cells. In vivo activity of MA49 against FLT3-ITD-positive leukemia cells is verified in a Danio rerio model. The degrader-induced loss of FLT3-ITD involves the pro-apoptotic BH3-only protein BIM and a previously unidentified degrader-induced depletion of protein-folding chaperones. The expression levels of HSP90 and HSP110 correlate with reduced AML patient survival (p < 0.1) and HSP90, HSP110, and BIM are linked to the expression of FLT3 in primary AML cells (p < 0.01). HSP90 suppresses degrader-induced FLT3-ITD elimination and thereby establishes a mechanistically defined feed-back circuit. [Abstract copyright: © 2024. The Author(s).

Biological Earth observation with animal sensors

Space-based tracking technology using low-cost miniature tags is now delivering data on fine-scale animal movement at near-global scale. Linked with remotely sensed environmental data, this offers a biological lens on habitat integrity and connectivity for conservation and human health; a global network of animal sentinels of environmen-tal change

[[alternative]]Lernziel Deutsch: Deutsch als fremdsprache

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[[alternative]]Lernziel Deutsch: Deutsch als fremdsprache

2册[[notice]]補正完畢[[booktype]]紙

Disputationum Theologicarum De Sacrificiis Satisfactionis Christi Pro Peccatis Totius Mundi Praestitae, Typis Firmissimis. Adversus recentiores Arianos seu Photinianos Satisfactionem Christi omnem pernegantes Decima Octava : In qua iterum obiectis Photinianis contra meritum Christi aliis respondendi modus demonstratur & continuatur

Quae In Collegio Disputationum Theologicarum ... ad d. 18. Ianuarii Anno MDCXVI. in ... Witebergensium Academia habebitur. Praeside Wolfgango Franzio ... Respondente Luca Hiebero ...Auch in: Franz, Wolfgang: Schola Sacrificiorum Patriarchalium Sacra, Hoc Est Aßertio solidißima, Satisfactionis a Domino nostro Jesu Christo, pro peccatis totius mundi, praestitae (Ausg. 1616 und 1617

Functional Analysis and Evolution Equations: Dedicated to Gunter Lumer

GA1/4nter Lumer was an outstanding mathematician whose work has great influence on the research community in mathematical analysis and evolution equations. He was at the origin of the breath-taking development the theory of semigroups saw after the pioneering book of Hille and Phillips of 1957. This volume contains invited contributions presenting the state of the art of these topics and reflecting the broad interests of GA1/4nter Lumer