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Chronic myeloproliferative neoplasms

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


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.

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Fig. 1: Supplementation of primary CMML cells with MN1 promotes engraftment in vivo.
Fig. 2: CMML-MN1 cells engraft secondary recipient mice and are serially transplantable.
Fig. 3: Clonal dominance of an NRAS-mutated subclone during serial transplantation of CMML#1-MN1 cells.
Fig. 4: Loss-of-function shRNA-screening identifies functional dependencies in CMML#1-MN1 cells.
Fig. 5: The MEK-inhibitor trametinib prolongs survival of CMML#1-MN1 mice when combined with azacitidine.


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We would like to thank all participating patients and contributing nurses and doctors, the staff of the Central Animal Facility of Hannover Medical School, and Martin Wichmann, Kerstin Görlich and Karin Battmer for their support. We acknowledge the assistance of the Cell Sorting Core Facility of Hannover Medical School supported in part by the Braukmann-Wittenberg-Herz-Stiftung and the Deutsche Forschungsgemeinschaft. This work was supported by an ERC grant under the European Union’s Horizon 2020 research and innovation program (No. 638035), by grants 109714 and 70112697 from Deutsche Krebshilfe; and DFG grants HE 5240/5–1, HE 5240/5–2, HE 5240/6–1, and HE 5240/6–2.

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Correspondence to Michael Heuser.

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Kloos, A., Mintzas, K., Winckler, L. et al. Effective drug treatment identified by in vivo screening in a transplantable patient-derived xenograft model of chronic myelomonocytic leukemia. Leukemia 34, 2951–2963 (2020).

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