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1. Polymethine Dye-Functionalized Nanoparticles for Targeting CML Stem Cells

Author

Philipp Ernst, Adrian T. Press, Mike Fischer, Vivien Günther, Christine Gräfe, Joachim H. Clement, Thomas Ernst, Ulrich S. Schubert, Jana Wotschadlo, Marc Lehmann, Christoph Enzensperger, Michael Bauer, and Andreas Hochhaus

Subjects
polymethine dyes, nanoparticles, CML, OATP1B3, OCT1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

In chronic myelogenous leukemia (CML), treatment with tyrosine kinase inhibitors (TKI) is unable to eradicate leukemic stem cells (LSC). Polymethine dye-functionalized nanoparticles can be internalized by specific cell types using transmembrane carrier proteins. In this study we investigated the uptake behavior of various polymethine dyes on leukemia cell lines and searched for carrier proteins that guide dye transport using RNA interference. The results show that the uptake of DY-635 is dependent on organic anion transport protein 1B3 (OATP1B3) in CML cells and immature myeloid precursor cells of CML patients. In contrast to nonspecific poly(lactide-co-glycolic acid) (PLGA) nanoparticle constructs, DY-635-functionalization of nanoparticles led to an uptake in CML cells. Investigation of these nanoparticles on bone marrow of CML patients showed a preferred uptake in LSC. The transcription of OATP1B3 is known to be induced under hypoxic conditions via the hypoxia-inducing factor 1 alpha (HIF1α), thus also in the stem cells niche. Since these cells have the potential to repopulate the bone marrow after CML treatment discontinuation, eliminating them by means of drug-loaded DY-635-functionalized PLGA nanoparticles deployed as a selective delivery system to LSC is highly relevant to the ongoing search for curative treatment options for CML patients.

Published
2020
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2. Modulation of FLT3-ITD Localization and Targeting of Distinct Downstream Signaling Pathways as Potential Strategies to Overcome FLT3-Inhibitor Resistance

Author

Maximilian Fleischmann, Mike Fischer, Ulf Schnetzke, Colin Fortner, Joanna Kirkpatrick, Florian H. Heidel, Andreas Hochhaus, and Sebastian Scholl

Subjects
AML, FLT3-ITD, HSP90, tunicamycin, 17-AAG, VPA, Cytology, QH573-671
Abstract

OBJECTIVES: Internal tandem duplications (ITDs) of the Fms-like tyrosine kinase 3 (FLT3) represent the most frequent molecular aberrations in acute myeloid leukemia (AML) and are associated with an inferior prognosis. The pattern of downstream activation by this constitutively activated receptor tyrosine kinase is influenced by the localization of FLT3-ITD depending on its glycosylation status. Different pharmacological approaches can affect FLT3-ITD-driven oncogenic pathways by the modulation of FLT3-ITD localization. AIMS: The objective of this study was to investigate the effects of N-glycosylation inhibitors (tunicamycin or 2-deoxy-D-glucose) or the histone deacetylase inhibitor valproic acid (VPA) on FLT3-ITD localization and downstream activity. We sought to determine the potential differences between the distinct FLT3-ITD variants, particularly concerning their susceptibility towards combined treatment by addressing either N-glycosylation and the heat shock protein 90 (HSP90) by 17-AAG, or by targeting the PI3K/AKT/mTOR pathway by rapamycin after treatment with VPA. METHODS: Murine Ba/F3 leukemia cell lines were stably transfected with distinct FLT3-ITD variants resulting in IL3-independent growth. These Ba/F3 FLT3-ITD cell lines or FLT3-ITD-expressing human MOLM13 cells were exposed to tunicamycin, 2-deoxy-D-glucose or VPA, and 17-AAG or rapamycin, and characterized in terms of downstream signaling by immunoblotting. FLT3 surface expression, apoptosis, and metabolic activity were analyzed by flow cytometry or an MTS assay. Proteome analysis by liquid chromatography–tandem mass spectrometry was performed to assess differential protein expression. RESULTS: The susceptibility of FLT3-ITD-expressing cells to 17-AAG after pre-treatment with tunicamycin or 2-deoxy-D-glucose was demonstrated. Importantly, in Ba/F3 cells that were stably expressing distinct FLT3-ITD variants that were located either in the juxtamembrane domain (JMD) or in the tyrosine kinase 1 domain (TKD1), response to the sequential treatments with tunicamycin and 17-AAG varied between individual FLT3-ITD motifs without dependence on the localization of the ITD. In all of the FLT3-ITD cell lines that were investigated, incubation with tunicamycin was accompanied by intracellular retention of FLT3-ITD due to the inhibition of glycosylation. In contrast, treatment of Ba/F3-FLT3-ITD cells with VPA was associated with a significant increase of FLT3-ITD surface expression depending on FLT3 protein synthesis. The allocation of FLT3 to different cellular compartments that was induced by tunicamycin, 2-deoxy-D-glucose, or VPA resulted in the activation of distinct downstream signaling pathways. Whole proteome analyses of Ba/F3 FLT3-ITD cells revealed up-regulation of the relevant chaperone proteins (e.g., calreticulin, calnexin, HSP90beta1) that are directly involved in the stabilization of FLT3-ITD or in its retention in the ER compartment. CONCLUSION: The allocation of FLT3-ITD to different cellular compartments and targeting distinct downstream signaling pathways by combined treatment with N-glycosylation and HSP90 inhibitors or VPA and rapamycin might represent new therapeutic strategies to overcome resistance towards tyrosine kinase inhibitors in FLT3-ITD-positive AML. The treatment approaches addressing N-glycosylation of FLT3-ITD appear to depend on patient-specific FLT3-ITD sequences, potentially affecting the efficacy of such pharmacological strategies.

Published
2021
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5. Polymorphisms of Dectin-1 and TLR2 Predispose to Invasive Fungal Disease in Patients with Acute Myeloid Leukemia.

Author

Mike Fischer, Baerbel Spies-Weisshart, Karin Schrenk, Bernd Gruhn, Susan Wittig, Anita Glaser, Andreas Hochhaus, Sebastian Scholl, and Ulf Schnetzke

Subjects
Medicine, Science
Abstract

Patients with acute myeloid leukemia (AML) who undergo induction chemotherapy are at high risk for invasive fungal disease (IFD). Dectin-1, a C-type lectin family member represents one of the most important pattern recognition receptors of the innate immune system and single nucleotide polymorphisms (SNPs) in the Dectin-1 gene have been associated with an increased risk of infectious complications. We sought to investigate the impact of three different Dectin-1 SNPs and one TLR2 SNP on developing IFD in 186 adult patients with newly diagnosed AML following anthracycline-based induction chemotherapy.Genotyping of Dectin-1 SNPs (rs16910526, rs3901533 and rs7309123) and TLR2 SNP (rs5743708) was performed by TaqMan method and pyrosequencing. IFD was defined according to the EORTC/MSG consensus guidelines. Multiple logistic regression analyses were applied to evaluate the association between the polymorphisms and the occurrence of pulmonary infections. Dectin-1 expression studies with SNP genotyped human monocytes were performed to elucidate susceptibility to IFD following chemotherapy.We could demonstrate that patients carrying the Dectin-1 SNP rs7309123 G/G (n = 47) or G/G and C/G (n = 133) genotype revealed a significant higher risk for developing both pneumonia in general (adjusted odds ratio (OR): 2.5; p = 0.014 and OR: 3.0, p = 0.004) and pulmonary IFD (OR: 2.6; p = 0.012 and OR: 2.4, p = 0.041, respectively). Patients carrying the TLR2 SNP rs5743708 (R753Q, GA/AA genotype, n = 12) also revealed a significantly higher susceptibility to pneumonia including IFD. Furthermore, Dectin-1 mRNA expression in human monocytes was lower following chemotherapy.To our best knowledge, this study represents the first analysis demonstrating that harbouring polymorphisms of Dectin-1 (rs7309123) or TLR2 (rs5743708) represents an independent risk factor of developing IFD in patients with AML undergoing induction chemotherapy.

Published
2016
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6. Cell cycle-dependent and -independent telomere shortening accompanies murine brain aging

Author

Alexandra Kretz, Christian Schmeer, Mike Fischer, Ronny Haenold, Martin Förster, Quratul Ain, Otto W. Witte, Tzvetanka Bondeva, and Diane Penndorf

Subjects
0301 basic medicine, Senescence, Aging, Telomerase, Protein subunit, Cell, Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, telomere length, medicine, Animals, cellular senescence, Telomerase reverse transcriptase, telomerase reverse transcriptase, RelA subunit of nuclear factor kappa B, brain aging, cell cycle, Mitosis, Telomere Shortening, Cerebral Cortex, Neurons, Cell Cycle, Transcription Factor RelA, Cell Biology, Cell cycle, Telomere, Cell biology, 030104 developmental biology, medicine.anatomical_structure, 030217 neurology & neurosurgery, Research Paper
Abstract

Replication-based telomere shortening during lifetime is species- and tissue-specific, however, its impact on healthy aging is unclear. In particular, the contribution of telomere truncation to the aging process of the CNS, where replicative senescence alone fails to explain organ aging due to low to absent mitotic activity of intrinsic populations, is undefined. Here, we assessed changes in relative telomere length in non-replicative and replicative neural brain populations and telomerase activity as a function of aging in C57BL/6 mice. Telomeres in neural cells and sub-selected neurons shortened with aging in a cell cycle-dependent and -independent manner, with preponderance in replicative moieties, implying that proliferation accelerates, but is not prerequisite for telomere shortening. Consistent with this telomere erosion, telomerase activity and nuclear TERT protein were not induced with aging. Knockdown of the Rela subunit of NF-κB, which controls both telomerase enzyme and subcellular TERT protein allocation, did also not influence telomerase activity or telomere length, in spite of its naive up-regulation selectively under aging conditions. We conclude that telomere instability is intrinsic to physiological brain aging beyond cell replication, and appears to occur independently of a functional interplay with NF-κB, but rather as a failure to induce or relocate telomerase.

Published
2018
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7. Umdenkfabrik : Wie Sie den Goldschatz der Mitarbeiterideen bergen

Author

Mike Fischer and Mike Fischer

Abstract

Wie denkt ein Unternehmer, der jenseits von Gier, reinem Profitstreben oder Mitarbeiterausbeutung einen Führungsstil entwickelt hat, der sein Team begeistert, es zu unternehmerischem Handeln sowie zur Ideenproduktion en masse anregt? Mike Fischer weiß, welche Ingredienzen es braucht, um ein erfolgreicher Unternehmer zu sein: Mut, um revolutionäre Ideen in funktionierende Geschäftsmodelle umzusetzen, Liebe zum Unternehmertum und zu den Menschen, mit denen er arbeitet, und eine Leidenschaft, die andere ansteckt. Mike Fischer ist Ausnahmeunternehmer und Querdenker aus Leidenschaft. Seit 30 Jahren ist er Fahrschulunternehmer, Gastronom, Bildungsträger, Auto- und Fachkräfteverleiher. Der Überflieger und Erfolgsredner strebt immer weiter - und ist zugleich ein bodenständiger Familienmensch, der nicht mehr verdient als die meisten Mitarbeiter seiner Firmen. Und vielleicht das Wichtigste: Er lebt - nachweislich -, wovon er erzählt. Aufgewachsen in der ehemaligen DDR gründete der Selfmade-Man nach der Wende aus dem Nichts seine Fahrschule, die heute zu den umsatzstärksten in Deutschland gehört. Mit damals fast undenkbaren Ideen wie einem Fahrschulinternat gelang ihm statt Umsatzrückgang durch die geburtenschwachen Jahrgänge eine Umsatzsteigerung von über 33 Prozent. Aus ganz Deutschland kommen seine Kunden nach Gera. Was er anpackt, wird zum Erfolg: So baut er etwa mit seiner Baufirma die Gebäude selbst, die er für seine Firmen braucht, aktuell das Projekt'FischerDorf'. Die Liste seiner Erfolge und Preise wird zwar ständig länger, doch viel interessanter ist, wie er seine Firmen aufgebaut hat und welcher Spirit sie trägt: sein unkonventioneller und leidenschaftlicher Führungsstil, der von Querdenken und Werten wie Ehrlichkeit, Fairness und Menschenliebe geprägt ist.

Published
2020

9. Erfolg hat, wer mit Liebe führt : Vom Egoismus zum Wir

Author

Mike Fischer and Mike Fischer

Abstract

Mit diesem Buch erhalten Sie das E-Book (pdf oder epub/mobi) inklusive! Endlich glücklich arbeiten – Potenzialentfaltung fördern Wenn Vorgesetzte ihre Mitarbeiter dazu anleiten, über sich hinauszuwachsen und besser zu werden als sie selbst, entsteht eine wunderbare Unternehmenskultur: Erfolg und Glück ist allen Beteiligten garantiert. Wie ein solches Unternehmen tickt, in dem sich Mitarbeitende am Sonntag schon auf Montag freuen, zeigt der Ausnahmeunternehmer Mike Fischer. Seit er »Liebe« als zentralen Baustein in seine unternehmerische Philosophie integriert hat, entwickelt sich eine unvorstellbare Dynamik in seinen Unternehmen, die zu unternehmerischer Spitzenleistung führt. Hier berichtet er offen über seine Strategien und Prinzipien, ohne die Rückschläge zu verheimlichen, die überwunden werden müssen, wenn ein grundlegender Kulturwandel eingeleitet werden soll.

Published
2019

10. Isoform localization of Dectin-1 regulates the signaling quality of anti-fungal immunity

Author

Mike, Fischer, Jörg P, Müller, Bärbel, Spies-Weisshart, Christine, Gräfe, Oliver, Kurzai, Kerstin, Hünniger, Andreas, Hochhaus, Sebastian, Scholl, and Ulf, Schnetzke

Subjects
Glycosylation, Microscopy, Confocal, Macrophages, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Flow Cytometry, Monocytes, Cell Line, Mycoses, Cytokines, Humans, Protein Isoforms, Lectins, C-Type, Signal Transduction
Abstract

Dectin-1 is recognized as a major receptor for fungal ß-glucans and contributes to anti-fungal immunity. Human monocyte populations express Dectin-1 isoforms A and B, which differ by the presence of a stalk region and its N-linked glycosylation site. Here, we analyzed the expression of both isoforms in human monocyte-derived cells. The cellular localization on cell lines stably expressing either Dectin-1 isoform A or B was studied by flow cytometry and confocal laser scanning microscopy. Intracellular protein signaling and cytokine production were analyzed by immunoblotting and cytometric bead array, respectively. Monocyte-derived cells showed cell type-specific expression of the two isoforms. Glycosylated Dectin-1 isoform A was predominantly localized at the cell surface, non-glycosylated isoform B was retained intracellularly. Inhibition of glycosylation resulted in efficient abrogation of cell surface expression of isoform A. Signaling quality following Dectin-1 stimulation was reduced in isoform B cells. Differential isoform specific cytokine secretion was observed by cytometric bead array. We show here that n-glycosylation of Dectin-1 is crucial for its cell surface expression and consequently signal transduction. Taken together, unique cytokine secretion and varying expression levels of human Dectin-1 isoforms on monocyte-derived cells may indicate distinct isoform usage as a cell type-specific mechanism of regulating anti-fungal immunity.

Published
2016

12. Erfolg hat, wer Regeln bricht : Wie Leidenschaft zu Spitzenleistung führt. Ein Ausnahmeunternehmer packt aus

Author

Mike Fischer and Mike Fischer

Abstract

Es geht auch anders Wie denkt ein Unternehmer, der jenseits von Gier, reinem Profitstreben oder Mitarbeiterausbeutung einen Führungsstil entwickelt hat, der sein Team begeistert, es zu unternehmerischem Handeln sowie zur Ideenproduktion en masse anregt? Mike Fischer erzählt emotional packend und kurzweilig eine unternehmerische Querdenker-Geschichte nach der anderen und packt Erfolgsgeheimnisse aus, ohne zu belehren. Ein inspirierendes Buch, das zur Nachahmung einlädt.

Published
2014

14. Paradoxical MAPK-activation in response to treatment with tyrosine kinase inhibitors in CML: flow cytometry loses track

Author

Ulf, Schnetzke, Mike, Fischer, Jochen J, Frietsch, Andreas, Finkensieper, Joachim H, Clement, Andreas, Hochhaus, and Paul, La Rosée

Subjects
Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Antigens, CD34, Flow Cytometry, Enzyme Activation, Mice, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Neoplastic Stem Cells, Tumor Cells, Cultured, Animals, Humans, Phosphorylation, Protein Kinase Inhibitors, Cell Line, Transformed
Abstract

Paradoxical activation of the MAP-kinases, ERK1, and ERK2 (ERK1/2) is observed in CML cell lines and primary CML patient cells treated with tyrosine kinase inhibitors (TKI) in vitro. The commonly accepted assumption is that activated ERK1/2 is key regulators of survival of leukemic cells treated with kinase inhibitors. Hence, paradoxical ERK1/2-activation may trigger resistance in vivo, which yet has to be shown. We therefore sought to establish a flow cytometric assay that enables us to measure paradoxical TKI-induced ERK1/2-activation on a single cell basis in primary CML cells.Side-by-side Western blot and intracellular flow cytometry (FCM) after in vitro exposure of cell lines and primary cells to nilotinib were performed. Detailed analysis of pre-analytical factors and the issue of compartmentalization of phosphorylated ERK1/2 by confocal laser scanning microscopy were performed.Results were conflicting in that pERK-activation was robustly detected in Western blot assays, but not when cells were analyzed by FCM despite well functioning positive and negative controls. This is in contrast to experiments on other targets such as phospho-CrkL, where also in our hands TKI-dependent inhibition of phosphorylation is trackable by both Western blot and FCM assays.To our knowledge this is the first report of discordant results in phospho-protein analysis in TKI-treated cells analyzed by Western blot vs. FCM. We speculate that a substance specific interaction interferes with fluorescence dependent methods seeking to track phosphorylated ERK1/2 in TKI-treated cells.

Published
2013

16. Strike-slip duplexes

Author

Mike Fischer and Nigel Woodcock

Subjects
geography, geography.geographical_feature_category, Physical model, Bedding, Slip vector, Geology, Thrust, Geometry, Imbrication, Fault (geology), Strike-slip tectonics, Perpendicular, Geotechnical engineering
Abstract

Strike-slip fault systems often contain zones of steep imbricate faults geometrically similar to imbricate fans and duplexes in dip-slip, thrust and normal, fault systems. They are evident in map view rather than in vertical sections. Examples of duplexes are cited from both active and ancient systems and from theoretical and physical models. Duplexes may form at bends on strike-slip faults by a process kinematically analogous to the sequential imbrication of ramps on dip-slip faults. However some may form, and many may initiate, as non-sequential ‘Riedel’ fractures at fault offsets or on straight fault segments. This process is more marked than in dip-slip systems where primary anisotropy such as bedding exerts more control on fault geometry. Strike-slip duplexes may be shunted along the fault system parallel to the regional slip vector. However, duplexes or individual horses will usually also move up or down perpendicular to the slip vector because of the unconstrained upper surface to the fault system. These factors mean that no section through a strike-slip system should be expected to area balance. The faults of strike-slip duplexes and imbricate fans may root in kinematically necessary low-dip faults or may converge downwards and appear in vertical sections as flower structures.

Published
1986
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