Effective drug treatment identified by in vivo screening in a transplantable patient-derived xenograft model of chronic myelomonocytic leukemia View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-06-24

AUTHORS

Arnold Kloos, Konstantinos Mintzas, Lina Winckler, Razif Gabdoulline, Yasmine Alwie, Nidhi Jyotsana, Nadine Kattre, Renate Schottmann, Michaela Scherr, Charu Gupta, Felix F. Adams, Adrian Schwarzer, Dirk Heckl, Axel Schambach, Suzan Imren, R. Keith Humphries, Arnold Ganser, Felicitas Thol, Michael Heuser

ABSTRACT

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. More... »

PAGES

2951-2963

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41375-020-0929-3

DOI

http://dx.doi.org/10.1038/s41375-020-0929-3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1128716333

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/32576961


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