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Παρασκευή 23 Ιουνίου 2017

NF1+/- hematopoietic cells accelerate malignant peripheral nerve sheath tumor development without altering chemotherapy response

Haploinsufficiency in the tumor suppressor NF1 contributes to the pathobiology of type 1 neurofibromatosis, but a related role has not been established in malignant peripheral nerve sheath tumors (MPNST) where NF1 mutations also occur. Patients with NF1-associated MPNST appear to have worse outcomes than patients with sporadic MPNST, but the mechanism underlying this correlation is not understood. To define the impact of stromal genetics on the biology of this malignancy, we developed unique mouse models that reflect the genetics of patient-associated MPNST. Specifically, we used adenovirus-cre injections to generate MPNST in Nf1 Flox/Flox ; Ink4a/Arf Flox/Flox and Nf1 Flox/- ; Ink4a/Arf Flox/Flox paired littermate mice to model tumors from NF1-wildtype and NF1-associated patients, respectively. In these models, Nf1 haploinsufficiency in hematopoietic cells accelerated tumor onset and increased levels of tumor-infiltrating immune cells comprised of CD11b+ cells, monocytes and mast cells. We observed that mast cells were also enriched in human NF1-associated MPNST. In a co-clinical trial to examine how the tumor microenvironment influences the response to multi-agent chemotherapy, we found that stromal Nf1 status had no effect. Taken together, our results clarify the role of the NF1-haploinsufficient tumor microenvironment in MPNST.

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