Proinflammatory microenvironment promotes lymphoma progression in mice with high megakaryocyte and TPO levels
Journal Title
Blood Advances
Publication Type
epub ahead of print
Abstract
Platelets have been shown to enhance the survival of lymphoma cell lines, but it is unclear if they play a role in lymphoma. Here we investigate a potential role for platelets and/or megakaryocytes in Eµ-myc lymphoma progression. Eµ-myc tumour cells were transplanted into recipient wild-type control mice, Mpl-/-, or TpoTg mice, which exhibit normal, low and high platelet and megakaryocyte counts, respectively. Transplanted TpoTg mice exhibited enhanced lymphoma progression with increased WBC counts, spleen and lymph node weights and enhanced liver infiltration when compared to wild-type. Conversely, tumour bearing Mpl-/- mice presented with reduced WBC counts, lymph node weights and less liver infiltration when compared to wild-type. Utilizing a Mpl-deficient thrombocytopenic immunocompromised mouse model, our results were confirmed with the human NHL GRANTA cell line. While we found that platelets and platelet released molecules supported Eµ-myc tumour cell survival in vitro, pharmacological inhibition of platelet function or anticoagulation in Eµ-myc transplanted wild-type mice did not improve disease outcome. Furthermore, transient platelet depletion or sustained Bcl-xL dependent thrombocytopenia did not alter lymphoma progression. Cytokine analysis of the bone marrow fluid microenvironment revealed increased levels of the proinflammatory molecule interleukin (IL)-1 in TpoTg mice, whereas levels were lowered in Mpl-/- mice. Moreover, RNA sequencing of blood-resident Eµ-myclymphoma cells from TpoTgand wild-type mice after tumour transplant revealed upregulation of hallmark gene sets associated with inflammatory response in TpoTg mice. We propose that a pro-inflammatory microenvironment in TpoTgmice promoted lymphoma progression.
Publisher
ASH
WEHI Research Division(s)
Bioinformatics; Blood Cells And Blood Cancer; Cancer Biology And Stem Cells; Advanced Technology And Biology
PubMed ID
36075025
Open Access at Publisher's Site
https://doi.org/10.1182/bloodadvances.2022007849
NHMRC Grants
NHMRC/1079250NHMRC/1113577NHMRC/1058344
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2022-09-19 02:39:05
Last Modified: 2022-09-19 02:46:19
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