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19 results on '"Knittel, G."'

1. Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies

Author

Thomalla, D., Beckmann, L., Grimm, C., Oliverio, M., Meder, L., Herling, C. D., Nieper, P., Feldmann, T., Merkel, O., Lorsy, E., Guerreiro, A. da Palma, von Jan, J., Kisis, I., Wasserburger, E., Claasen, J., Faitschuk-Meyer, E., Altmueller, J., Nuernberg, P., Yang, T. -P., Lienhard, M., Herwig, R., Kreuzer, K. -A., Pallasch, C. P., Buettner, R., Schaefer, S. C., Hartley, J., Abken, H., Peifer, M., Kashkar, H., Knittel, G., Eichhorst, B., Ullrich, R. T., Herling, M., Reinhardt, H. C., Hallek, M., Schweiger, M. R., Frenzel, L. P., Thomalla, D., Beckmann, L., Grimm, C., Oliverio, M., Meder, L., Herling, C. D., Nieper, P., Feldmann, T., Merkel, O., Lorsy, E., Guerreiro, A. da Palma, von Jan, J., Kisis, I., Wasserburger, E., Claasen, J., Faitschuk-Meyer, E., Altmueller, J., Nuernberg, P., Yang, T. -P., Lienhard, M., Herwig, R., Kreuzer, K. -A., Pallasch, C. P., Buettner, R., Schaefer, S. C., Hartley, J., Abken, H., Peifer, M., Kashkar, H., Knittel, G., Eichhorst, B., Ullrich, R. T., Herling, M., Reinhardt, H. C., Hallek, M., Schweiger, M. R., and Frenzel, L. P.

Abstract

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter's syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.

Published
2022

2. Targeting transcription-coupled nucleotide excision repair overcomes resistance in chronic lymphocytic leukemia

Author

Lohmann, G., Vasyutina, E., Bloehdorn, J., Reinart, N., Schneider, J. I., Babu, V., Knittel, G., Crispatzu, G., Mayer, P., Prinz, C., Muenzner, J. K., Biersack, B., Efremov, D. G., Chessa, L., Herling, C. D., Stilgenbauer, S., Hallek, M., Schobert, R., Reinhardt, H. C., Schumacher, B., Herling, M., Lohmann, G., Vasyutina, E., Bloehdorn, J., Reinart, N., Schneider, J. I., Babu, V., Knittel, G., Crispatzu, G., Mayer, P., Prinz, C., Muenzner, J. K., Biersack, B., Efremov, D. G., Chessa, L., Herling, C. D., Stilgenbauer, S., Hallek, M., Schobert, R., Reinhardt, H. C., Schumacher, B., and Herling, M.

Abstract

Treatment resistance becomes a challenge at some point in the course of most patients with chronic lymphocytic leukemia (CLL). This applies to fludarabine-based regimens, and is also an increasing concern in the era of more targeted therapies. As cells with low-replicative activity rely on repair that triggers checkpoint-independent noncanonical pathways, we reasoned that targeting the nucleotide excision repair (NER) reaction addresses a vulnerability of CLL and might even synergize with fludarabine, which blocks the NER gap-filling step. We interrogated here especially the replication-independent transcription-coupled-NER ((TC)-NER) in prospective trial patients, primary CLL cultures, cell lines and mice. We screen selected (TC)-NER-targeting compounds as experimental (illudins) or clinically approved (trabectedin) drugs. They inflict transcription-stalling DNA lesions requiring TC-NER either for their removal (illudins) or for generation of lethal strand breaks (trabectedin). Genetically defined systems of NER deficiency confirmed their specificity. They selectively and efficiently induced cell death in CLL, irrespective of high-risk cytogenetics, IGHV status or clinical treatment history, including resistance. The substances induced ATM/p53-independent apoptosis and showed marked synergisms with fludarabine. Trabectedin additionally perturbed stromal-cell protection and showed encouraging antileukemic profiles even in aggressive and transforming murine CLL. This proof-of-principle study established (TC)-NER as a mechanism to be further exploited to resensitize CLL cells.

Published
2017

3. Novel models of high-risk CLL reveal an actionable PARP1 dependence in ATM-defective CLL in vivo

Author

Knittel, G., Korovkina, D., Liedgens, P., Rehkaemper, T., Fritz, C., Torgovnick, A., Al-Baldawi, Y., Al-Maarri, M., Cun, Y., Fedorchenko, O., Riabinska, A., Beleggia, F., Nguyen, P. -H., Wunderlich, F. T., Ortmann, M., Montesinos-Rongen, M., Tausch, E., Stilgenbauer, S., Frenzel, L., Herling, M., Herling, C., Bahlo, J., Hallek, M., Peifer, M., Buettner, R., Persigehl, T., Reinhardt, H. C., Knittel, G., Korovkina, D., Liedgens, P., Rehkaemper, T., Fritz, C., Torgovnick, A., Al-Baldawi, Y., Al-Maarri, M., Cun, Y., Fedorchenko, O., Riabinska, A., Beleggia, F., Nguyen, P. -H., Wunderlich, F. T., Ortmann, M., Montesinos-Rongen, M., Tausch, E., Stilgenbauer, S., Frenzel, L., Herling, M., Herling, C., Bahlo, J., Hallek, M., Peifer, M., Buettner, R., Persigehl, T., and Reinhardt, H. C.

Published
2017

5. Restoration of Atm induces lymphoma regression in vivo and is mediated by cell autonomous and non-cell autonomous mechanisms

Author

Riabinska, A., Schmitt, A., Fritz, C., Knittel, G., Torgovnick, A., Heneweer, C., Wittersheim, M., Frenzel, L., Wunderlich, C., Jachimowicz, R., Merseburg, A., Persigehl, T., Wunderlich, T., Buettner, R., Reinhardt, H. C., Riabinska, A., Schmitt, A., Fritz, C., Knittel, G., Torgovnick, A., Heneweer, C., Wittersheim, M., Frenzel, L., Wunderlich, C., Jachimowicz, R., Merseburg, A., Persigehl, T., Wunderlich, T., Buettner, R., and Reinhardt, H. C.

Published
2017

6. Targeting transcription-coupled nucleotide excision repair overcomes resistance in chronic lymphocytic leukemia

Author

Lohmann, G., Vasyutina, E., Bloehdorn, J., Reinart, N., Schneider, J. I., Babu, V., Knittel, G., Crispatzu, G., Mayer, P., Prinz, C., Muenzner, J. K., Biersack, B., Efremov, D. G., Chessa, L., Herling, C. D., Stilgenbauer, S., Hallek, M., Schobert, R., Reinhardt, H. C., Schumacher, B., Herling, M., Lohmann, G., Vasyutina, E., Bloehdorn, J., Reinart, N., Schneider, J. I., Babu, V., Knittel, G., Crispatzu, G., Mayer, P., Prinz, C., Muenzner, J. K., Biersack, B., Efremov, D. G., Chessa, L., Herling, C. D., Stilgenbauer, S., Hallek, M., Schobert, R., Reinhardt, H. C., Schumacher, B., and Herling, M.

Abstract

Treatment resistance becomes a challenge at some point in the course of most patients with chronic lymphocytic leukemia (CLL). This applies to fludarabine-based regimens, and is also an increasing concern in the era of more targeted therapies. As cells with low-replicative activity rely on repair that triggers checkpoint-independent noncanonical pathways, we reasoned that targeting the nucleotide excision repair (NER) reaction addresses a vulnerability of CLL and might even synergize with fludarabine, which blocks the NER gap-filling step. We interrogated here especially the replication-independent transcription-coupled-NER ((TC)-NER) in prospective trial patients, primary CLL cultures, cell lines and mice. We screen selected (TC)-NER-targeting compounds as experimental (illudins) or clinically approved (trabectedin) drugs. They inflict transcription-stalling DNA lesions requiring TC-NER either for their removal (illudins) or for generation of lethal strand breaks (trabectedin). Genetically defined systems of NER deficiency confirmed their specificity. They selectively and efficiently induced cell death in CLL, irrespective of high-risk cytogenetics, IGHV status or clinical treatment history, including resistance. The substances induced ATM/p53-independent apoptosis and showed marked synergisms with fludarabine. Trabectedin additionally perturbed stromal-cell protection and showed encouraging antileukemic profiles even in aggressive and transforming murine CLL. This proof-of-principle study established (TC)-NER as a mechanism to be further exploited to resensitize CLL cells.

Published
2017

8. Restoration of Atm induces lymphoma regression in vivo and is mediated by cell autonomous and non-cell autonomous mechanisms

Author

Riabinska, A., Schmitt, A., Fritz, C., Knittel, G., Torgovnick, A., Heneweer, C., Wittersheim, M., Frenzel, L., Wunderlich, C., Jachimowicz, R., Merseburg, A., Persigehl, T., Wunderlich, T., Buettner, R., Reinhardt, H. C., Riabinska, A., Schmitt, A., Fritz, C., Knittel, G., Torgovnick, A., Heneweer, C., Wittersheim, M., Frenzel, L., Wunderlich, C., Jachimowicz, R., Merseburg, A., Persigehl, T., Wunderlich, T., Buettner, R., and Reinhardt, H. C.

Published
2017

9. Novel models of high-risk CLL reveal an actionable PARP1 dependence in ATM-defective CLL in vivo

Author

Knittel, G., Korovkina, D., Liedgens, P., Rehkaemper, T., Fritz, C., Torgovnick, A., Al-Baldawi, Y., Al-Maarri, M., Cun, Y., Fedorchenko, O., Riabinska, A., Beleggia, F., Nguyen, P. -H., Wunderlich, F. T., Ortmann, M., Montesinos-Rongen, M., Tausch, E., Stilgenbauer, S., Frenzel, L., Herling, M., Herling, C., Bahlo, J., Hallek, M., Peifer, M., Buettner, R., Persigehl, T., Reinhardt, H. C., Knittel, G., Korovkina, D., Liedgens, P., Rehkaemper, T., Fritz, C., Torgovnick, A., Al-Baldawi, Y., Al-Maarri, M., Cun, Y., Fedorchenko, O., Riabinska, A., Beleggia, F., Nguyen, P. -H., Wunderlich, F. T., Ortmann, M., Montesinos-Rongen, M., Tausch, E., Stilgenbauer, S., Frenzel, L., Herling, M., Herling, C., Bahlo, J., Hallek, M., Peifer, M., Buettner, R., Persigehl, T., and Reinhardt, H. C.

Published
2017

10. ESTABLISHMENT OF A PRE-CLINICAL IN VIVO PLATFORM SPANNING LOW-RISK TO HIGH-RISK CLL

Author

Knittel, G., Korovkina, D., Liedgens, P., Fritz, C., Al-Baldawi, Y., Bahlo, J., Herling, C., Eichhorst, B., Hallek, M., Persigehl, T., Buettner, R., Reinhardt, H. C., Knittel, G., Korovkina, D., Liedgens, P., Fritz, C., Al-Baldawi, Y., Bahlo, J., Herling, C., Eichhorst, B., Hallek, M., Persigehl, T., Buettner, R., and Reinhardt, H. C.

Published
2016

11. B CELL-SPECIFIC CONDITIONAL EXPRESSION OF MYD88P.L252P LEADS TO THE DEVELOPMENT OF DIFFUSE LARGE B CELL LYMPHOMA IN MICE

Author

Knittel, G., Liedgens, P., Korovkina, D., Seeger, J. M., Al-Baldawi, Y., Vlantis, K., Fritz, C., Schaefer, S. C., Klatt, A., Scheel, A., Al-Maarri, M., Bezhanova, S., Montesinos-Rongen, M., Wolz, O. O., Reimann, M., Lohneis, P., Weber, A. N., Wunderlich, F. T., Pasparakis, M., Buettner, R., Persigehl, T., Schmitt, C. A., Odenthal, M., Frenzel, L. P., Kashkar, H., Reinhardt, H. C., Knittel, G., Liedgens, P., Korovkina, D., Seeger, J. M., Al-Baldawi, Y., Vlantis, K., Fritz, C., Schaefer, S. C., Klatt, A., Scheel, A., Al-Maarri, M., Bezhanova, S., Montesinos-Rongen, M., Wolz, O. O., Reimann, M., Lohneis, P., Weber, A. N., Wunderlich, F. T., Pasparakis, M., Buettner, R., Persigehl, T., Schmitt, C. A., Odenthal, M., Frenzel, L. P., Kashkar, H., and Reinhardt, H. C.

Published
2016

12. B cell-specific conditional expression of Myd88 p.L252P leads to the development of diffuse large B cell lymphoma in mice

Author

Knittel, G., Liedgens, P., Korovkina, D., Seeger, J. M., Al-Baldawi, Y., Al-Maarri, M., Fritz, C., Vlantis, K., Bezhanova, S., Scheel, A. H., Wolz, O. -O., Reimann, M., Moeller, P., Lopez, C., Staudt, L. M., Ortmann, M., Pasparakis, M., Siebert, R., Schmitt, C. A., Klatt, A. R., Wunderlich, F. T., Schaefer, S. C., Persigehl, T., Montesinos-Rongen, M., Odenthal, M., Buettner, R., Frenzel, L. P., Kashkar, H., Reinhardt, H. C., Knittel, G., Liedgens, P., Korovkina, D., Seeger, J. M., Al-Baldawi, Y., Al-Maarri, M., Fritz, C., Vlantis, K., Bezhanova, S., Scheel, A. H., Wolz, O. -O., Reimann, M., Moeller, P., Lopez, C., Staudt, L. M., Ortmann, M., Pasparakis, M., Siebert, R., Schmitt, C. A., Klatt, A. R., Wunderlich, F. T., Schaefer, S. C., Persigehl, T., Montesinos-Rongen, M., Odenthal, M., Buettner, R., Frenzel, L. P., Kashkar, H., and Reinhardt, H. C.

Published
2016

13. B CELL-SPECIFIC CONDITIONAL EXPRESSION OF MYD88P.L252P LEADS TO THE DEVELOPMENT OF DIFFUSE LARGE B CELL LYMPHOMA IN MICE

Author

Knittel, G., Liedgens, P., Korovkina, D., Seeger, J. M., Al-Baldawi, Y., Vlantis, K., Fritz, C., Schaefer, S. C., Klatt, A., Scheel, A., Al-Maarri, M., Bezhanova, S., Montesinos-Rongen, M., Wolz, O. O., Reimann, M., Lohneis, P., Weber, A. N., Wunderlich, F. T., Pasparakis, M., Buettner, R., Persigehl, T., Schmitt, C. A., Odenthal, M., Frenzel, L. P., Kashkar, H., Reinhardt, H. C., Knittel, G., Liedgens, P., Korovkina, D., Seeger, J. M., Al-Baldawi, Y., Vlantis, K., Fritz, C., Schaefer, S. C., Klatt, A., Scheel, A., Al-Maarri, M., Bezhanova, S., Montesinos-Rongen, M., Wolz, O. O., Reimann, M., Lohneis, P., Weber, A. N., Wunderlich, F. T., Pasparakis, M., Buettner, R., Persigehl, T., Schmitt, C. A., Odenthal, M., Frenzel, L. P., Kashkar, H., and Reinhardt, H. C.

Published
2016

14. ESTABLISHMENT OF A PRE-CLINICAL IN VIVO PLATFORM SPANNING LOW-RISK TO HIGH-RISK CLL

Author

Knittel, G., Korovkina, D., Liedgens, P., Fritz, C., Al-Baldawi, Y., Bahlo, J., Herling, C., Eichhorst, B., Hallek, M., Persigehl, T., Buettner, R., Reinhardt, H. C., Knittel, G., Korovkina, D., Liedgens, P., Fritz, C., Al-Baldawi, Y., Bahlo, J., Herling, C., Eichhorst, B., Hallek, M., Persigehl, T., Buettner, R., and Reinhardt, H. C.

Published
2016

15. B cell-specific conditional expression of Myd88 p.L252P leads to the development of diffuse large B cell lymphoma in mice

Author

Knittel, G., Liedgens, P., Korovkina, D., Seeger, J. M., Al-Baldawi, Y., Al-Maarri, M., Fritz, C., Vlantis, K., Bezhanova, S., Scheel, A. H., Wolz, O. -O., Reimann, M., Moeller, P., Lopez, C., Staudt, L. M., Ortmann, M., Pasparakis, M., Siebert, R., Schmitt, C. A., Klatt, A. R., Wunderlich, F. T., Schaefer, S. C., Persigehl, T., Montesinos-Rongen, M., Odenthal, M., Buettner, R., Frenzel, L. P., Kashkar, H., Reinhardt, H. C., Knittel, G., Liedgens, P., Korovkina, D., Seeger, J. M., Al-Baldawi, Y., Al-Maarri, M., Fritz, C., Vlantis, K., Bezhanova, S., Scheel, A. H., Wolz, O. -O., Reimann, M., Moeller, P., Lopez, C., Staudt, L. M., Ortmann, M., Pasparakis, M., Siebert, R., Schmitt, C. A., Klatt, A. R., Wunderlich, F. T., Schaefer, S. C., Persigehl, T., Montesinos-Rongen, M., Odenthal, M., Buettner, R., Frenzel, L. P., Kashkar, H., and Reinhardt, H. C.

Published
2016

18. GPS-Squitter Automatic Dependent Surveillance Broadcast: Flight Testing in the Gulf of Mexico

Author

MASSACHUSETTS INST OF TECH LEXINGTON LINCOLN LAB, Boisevert, R. E., Burrows, M. L., Bussolari, S. R., Knittel, G. H., Owen, M. R., MASSACHUSETTS INST OF TECH LEXINGTON LINCOLN LAB, Boisevert, R. E., Burrows, M. L., Bussolari, S. R., Knittel, G. H., and Owen, M. R.

Abstract

During November - December 1994, MIT Lincoln Laboratory conducted a field evaluation of the air surveillance capabilities of GPS-Squitter in the Gulf of Mexico. Three squitter ground stations were located in the vicinity of Morgan City, Louisiana, for this evaluation: two were located on offshore oil platforms, and the third was located at an onshore heliport. Surveillance coverage tests were flown over the Gulf with three test aircraft-two helicopters and one Cessna 421 fixed- wing aircraft. The helicopters flew at altitudes ranging from 100 to 2000 feet above sea level and the Cessna flew at 7500 and 20,000 feet. Extended squitter messages broadcast by each of the test aircraft provided aircraft position and identification. This report documents results of these tests and compares measured coverage to predicted coverage from the ground stations. Based on the good agreement between predicted and measured performance, a description of a possible operational system is included that would provide surveillance of the entire Gulf region serviced by oil platform helicopters. The report concludes that GPS- Squitter is a near-term option for providing accurate, real-time surveillance of aircraft operating in the offshore airspace in the Gulf of Mexico., Original contains color plates: All DTIC/NTIS reproductions will be in black and white.

Published
1995

19. Phase II Netted Radar Demonstration

Author

MASSACHUSETTS INST OF TECH LEXINGTON LINCOLN LAB, Knittel, G H, MASSACHUSETTS INST OF TECH LEXINGTON LINCOLN LAB, and Knittel, G H

Abstract

This Project Report describes the system configuration which is being used for the Phase II Netted Radar Demonstration currently under way at Fort Sill, Oklahoma. A brief description of the demonstration scenarios is also included.

Published
1980

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