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1,356 results on '"Koeffler, H P"'

184. Homozygous Deletion of the p16 Gene in Childhood Acute Lymphoblastic Leukemia

Author

Seriu, T., primary, Takeuchi, S., additional, Miller, C. W., additional, Tobler, A., additional, Janssen, J. W. G., additional, Reiter, A., additional, Ludwig, W.-D., additional, Zimmermann, M., additional, Schwaller, J., additional, Lee, E., additional, Miyoshi, I., additional, Koeffler, H. P., additional, and Bartram, C. R., additional

Published
1997
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190. Targeted siRNA nanocarrier: a platform technology for cancer treatment

Author

Bäumer, Nicole, Tiemann, Jessica, Scheller, Annika, Meyer, Theresa, Wittmann, Lisa, Suburu, Matias Ezequiel Gutierrez, Greune, Lilo, Peipp, Matthias, Kellmann, Neele, Gumnior, Annika, Brand, Caroline, Hartmann, Wolfgang, Rossig, Claudia, Müller-Tidow, Carsten, Neri, Dario, Strassert, Cristian A., Rüter, Christian, Dersch, Petra, Lenz, Georg, Koeffler, H. Phillip, Berdel, Wolfgang E., and Bäumer, Sebastian

Abstract

The small arginine-rich protein protamine condenses complete genomic DNA into the sperm head. Here, we applied its high RNA binding capacity for spontaneous electrostatic assembly of therapeutic nanoparticles decorated with tumour-cell-specific antibodies for efficiently targeting siRNA. Fluorescence microscopy and DLS measurements of these nanocarriers revealed the formation of a vesicular architecture that requires presence of antibody-protamine, defined excess of free SMCC-protamine, and anionic siRNA to form. Only these complex nanoparticles were efficient in the treatment of non-small-cell lung cancer (NSCLC) xenograft models, when the oncogene KRAS was targeted via EGFR-mediated delivery. To show general applicability, we used the modular platform for IGF1R-positive Ewing sarcomas. Anti-IGR1R-antibodies were integrated into an antibody-protamine nanoparticle with an siRNA specifically against the oncogenic translocation product EWS/FLI1. Using these nanoparticles, EWS/FLI1 knockdown blocked in vitro and in vivo growth of Ewing sarcoma cells. We conclude that these antibody-protamine-siRNA nanocarriers provide a novel platform technology to specifically target different cell types and yet undruggable targets in cancer therapy by RNAi.

Published
2022
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192. Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates

Author

Koeffler H Phillip, Saito Tsuyako, and Gombart Adrian F

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background About 45% of the human genome is comprised of mobile transposable elements or "junk DNA". The exaptation or co-option of these elements to provide important cellular functions is hypothesized to have played a powerful force in evolution; however, proven examples are rare. An ancient primate-specific Alu short interspersed element (SINE) put the human CAMP gene under the regulation of the vitamin D pathway by providing a perfect vitamin D receptor binding element (VDRE) in its promoter. Subsequent studies demonstrated that the vitamin D-cathelicidin pathway may be a key component of a novel innate immune response of human to infection. The lack of evolutionary conservation in non-primate mammals suggested that this is a primate-specific adaptation. Evidence for evolutionary conservation of this regulation in additional primate lineages would provide strong evidence that the TLR2/1-vitamin D-cathelicidin pathway evolved as a biologically important immune response mechanism protecting human and non-human primates against infection. Results PCR-based amplification of the Alu SINE from human and non-human primate genomic DNA and subsequent sequence analysis, revealed perfect structural conservation of the VDRE in all primates examined. Reporter gene studies and induction of the endogenous CAMP gene in Rhesus macaque peripheral blood mononuclear cells demonstrated that the VDREs were conserved functionally. In addition, New World monkeys (NWMs) have maintained additional, functional steroid-hormone receptor binding sites in the AluSx SINE that confer retinoic acid responsiveness and provide potential thyroid hormone receptor binding sites. These sites were less well-conserved during human, ape and Old World monkey (OWM) evolution and the human CAMP gene does not respond to either retinoic acid or thyroid hormone. Conclusion We demonstrated that the VDRE in the CAMP gene originated from the exaptation of an AluSx SINE in the lineage leading to humans, apes, OWMs and NWMs and remained under purifying selection for the last 55–60 million years. We present convincing evidence of an evolutionarily fixed, Alu-mediated divergence in steroid hormone nuclear receptor gene regulation between humans/primates and other mammals. Evolutionary selection to place the primate CAMP gene under regulation of the vitamin D pathway potentiates the innate immune response and may counter the anti-inflammatory properties of vitamin D.

Published
2009
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195. Author Correction: Metabolic gatekeeper function of B-lymphoid transcription factors (Nature (2017) DOI: 10.1038/nature21076)

Author

Chan L. N., Chan, L, Chen, Z, Braas, D, Lee, J, Xiao, G, Geng, H, Cosgun, K, Hurtz, C, Shojaee, S, Cazzaniga, V, Schjerven, H, Ernst, T, Hochhaus, A, Kornblau, S, Konopleva, M, Pufall, M, Cazzaniga, G, Liu, G, Milne, T, Koeffler, H, Ross, T, Sanchez-Garcia, I, Borkhardt, A, Yamamoto, K, Dickins, R, Graeber, T, Muschen, M, Chan L. N., Chen Z., Braas D., Lee J. -W., Xiao G., Geng H., Cosgun K. N., Hurtz C., Shojaee S., Cazzaniga V., Schjerven H., Ernst T., Hochhaus A., Kornblau S. M., Konopleva M., Pufall M. A., Cazzaniga G., Liu G. J., Milne T. A., Koeffler H. P., Ross T. S., Sanchez-Garcia I., Borkhardt A., Yamamoto K. R., Dickins R. A., Graeber T. G., Muschen M., Chan L. N., Chan, L, Chen, Z, Braas, D, Lee, J, Xiao, G, Geng, H, Cosgun, K, Hurtz, C, Shojaee, S, Cazzaniga, V, Schjerven, H, Ernst, T, Hochhaus, A, Kornblau, S, Konopleva, M, Pufall, M, Cazzaniga, G, Liu, G, Milne, T, Koeffler, H, Ross, T, Sanchez-Garcia, I, Borkhardt, A, Yamamoto, K, Dickins, R, Graeber, T, Muschen, M, Chan L. N., Chen Z., Braas D., Lee J. -W., Xiao G., Geng H., Cosgun K. N., Hurtz C., Shojaee S., Cazzaniga V., Schjerven H., Ernst T., Hochhaus A., Kornblau S. M., Konopleva M., Pufall M. A., Cazzaniga G., Liu G. J., Milne T. A., Koeffler H. P., Ross T. S., Sanchez-Garcia I., Borkhardt A., Yamamoto K. R., Dickins R. A., Graeber T. G., and Muschen M.

Abstract

In Fig. 3c of this Letter, the the effects of CRISPR-Cas9-mediated deletion of NR3C1, TXNIP and CNR2 in patient-derived B-lineage leukaemia cells were shown. For curves depicting NR3C1 (left graph), data s for TXNIP (middle graph) were inadvertently plotted. This figure has been corrected online, and the original Fig. 3c is shown as Supplementary Information to this Amendment for transparency. The error does not affect the conclusions of the Letter. In addition, Source Data files have been added for the Figs. 1-4 and Extended Data Figs. 1-10 of the original Letter.

Published
2018

196. MNK1 and MNK2 enforce expression of E2F1, FOXM1, and WEE1 to drive soft tissue sarcoma

Author

Ke, Xin-Yu, Chen, Ye, Tham, Valarie Yu-Yan, Lin, Ruby Yu-Tong, Dakle, Pushkar, Nacro, Kassoum, Puhaindran, Mark Edward, Houghton, Peter, Pang, Angela, Lee, Victor Kwanmin, Ding, Ling-Wen, Gery, Sigal, Hill, Jeffrey, Chen, Leilei, Xu, Liang, and Koeffler, H. Phillip

Abstract

Soft tissue sarcoma (STS) is a heterogeneous disease that arises from connective tissues. Clinical outcome of patients with advanced tumors especially de-differentiated liposarcoma and uterine leiomyosarcoma remains unsatisfactory, despite intensive treatment regimens including maximal surgical resection, radiation, and chemotherapy. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) have been shown to contribute to oncogenic translation via phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). However, little is known about the role of MNK1/2 and their downstream targets in STS. In this study, we show that depletion of either MNK1 or MNK2 suppresses cell viability, anchorage-independent growth, and tumorigenicity of STS cells. We also identify a compelling antiproliferative efficacy of a novel, selective MNK inhibitor ETC-168. Cellular responsiveness of STS cells to ETC-168 correlates positively with that of phosphorylated ribosomal protein S6 (RPS6). Mirroring MNK1/2 silencing, ETC-168 treatment strongly blocks eIF4E phosphorylation and represses expression of sarcoma-driving onco-proteins including E2F1, FOXM1, and WEE1. Moreover, combination of ETC-168 and MCL1 inhibitor S63845 exerts a synergistic antiproliferative activity against STS cells. In summary, our study reveals crucial roles of MNK1/2 and their downstream targets in STS tumorigenesis. Our data encourage further clinical translation of MNK inhibitors for STS treatment.

Published
2021
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200. Mitophagy is a novel protective mechanism for drug-tolerant persister (DTP) cancer cells

Author

Li, Yun, Chen, Hengxing, Lu, Daning, Koeffler, H. Phillip, Zhang, Yin, and Yin, Dong

Abstract

ABSTRACTDrug-tolerant persister (DTP) cancer cells drive residual tumor and relapse. However, the mechanisms underlying DTP state development are largely unexplored. In a recent study, we determined that PINK1-mediated mitophagy favors DTP generation in the context of MAPK inhibition therapy. DTP cells that persist in the presence of a MAPK inhibitor exhibit mitochondriadependent metabolism. During DTP state development, MYC depletion alleviates the transcriptional repression of PINK1, resulting in PINK1 upregulation and mitophagy activation. PINK1-mediated mitophagy is essential for mitochondrial homeostasis in DTP cells. Either knockdown of PINK1 or inhibition of mitophagy eradicates DTP cells and achieves complete responses to MAPK inhibition therapy. This study reveals a novel role of mitophagy as a protective mechanism for DTP development.

Published
2023
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