Effective drug treatment identified by in vivo screening in a transplantable patient-derived xenograft model of chronic myelomonocytic leukemia
| Autor: | Arnold Ganser, Lina Winckler, Axel Schambach, Felicitas Thol, Adrian Schwarzer, Charu Gupta, Konstantinos Mintzas, Nidhi Jyotsana, Suzan Imren, R. Keith Humphries, Nadine Kattre, Arnold Kloos, Michael Heuser, Felix F. Adams, Razif Gabdoulline, Renate Schottmann, Dirk Heckl, Michaela Scherr, Yasmine Alwie |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Neuroblastoma RAS viral oncogene homolog Cancer Research Pyridones Azacitidine Drug Evaluation Preclinical Chronic myelomonocytic leukemia Antineoplastic Agents Pyrimidinones Gene mutation Article GTP Phosphohydrolases Clonal Evolution Mice 03 medical and health sciences 0302 clinical medicine In vivo hemic and lymphatic diseases Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans RNA Small Interfering Receptor Notch1 Protein Kinase Inhibitors Trametinib Oncogene business.industry Membrane Proteins Drug Synergism Leukemia Myelomonocytic Chronic Hematology medicine.disease Xenograft Model Antitumor Assays 3. Good health Transplantation Disease Models Animal 030104 developmental biology Oncology 030220 oncology & carcinogenesis Mutation Cancer research Female business medicine.drug |
| Zdroj: | Leukemia |
| DOI: | 10.25673/108792 |
| Popis: | To establish novel and effective treatment combinations for chronic myelomonocytic leukemia (CMML) preclinically, we hypothesized that supplementation of CMML cells with the human oncogene Meningioma 1 (MN1) promotes expansion and serial transplantability in mice, while maintaining the functional dependencies of these cells on their original genetic profile. Using lentiviral expression of MN1 for oncogenic supplementation and transplanting transduced primary mononuclear CMML cells into immunocompromised mice, we established three serially transplantable CMML-PDX models with disease-related gene mutations that recapitulate the disease in vivo. Ectopic MN1 expression was confirmed to enhance the proliferation of CMML cells, which otherwise did not engraft upon secondary transplantation. Furthermore, MN1-supplemented CMML cells were serially transplantable into recipient mice up to 5 generations. This robust engraftment enabled an in vivo RNA interference screening targeting CMML-related mutated genes including NRAS, confirming that their functional relevance is preserved in the presence of MN1. The novel combination treatment with azacitidine and the MEK-inhibitor trametinib additively inhibited ERK-phosphorylation and thus depleted the signal from mutated NRAS. The combination treatment significantly prolonged survival of CMML mice compared to single-agent treatment. Thus, we identified the combination of azacitidine and trametinib as an effective treatment in NRAS-mutated CMML and propose its clinical development. |
| Databáze: | OpenAIRE |
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