Proinflammatory microenvironment promotes lymphoma progression in mice with high megakaryocyte and TPO levels
- Author(s)
- Au, AE; Corbin, J; Lebois, M; Gangatirkar, P; Yassinson, F; Hyslop, SR; Cannon, P; Mason, KD; Li-Wai-Suen, CSN; Garnham, AL; Moujalled, D; Cimmino, L; Alexander, WS; Josefsson, EC;
- Details
- Publication Year 2023-04-25,Volume 7,Issue #8,Page 1560-1571
- Journal Title
- Blood Advances
- Publication Type
- Research article
- Abstract
- Platelets have been shown to enhance the survival of lymphoma cell lines. However, it remains unclear whether they play a role in lymphoma. Here, we investigated the potential role of platelets and/or megakaryocytes in the progression of Emu-myc lymphoma. Emu-myc tumor cells were transplanted into recipient wild-type (WT) control, Mpl-/-, or TpoTg mice, which exhibited normal, low, and high platelet and megakaryocyte counts, respectively. TpoTg mice that underwent transplantation exhibited enhanced lymphoma progression with increased white blood cell (WBC) counts, spleen and lymph node weights, and enhanced liver infiltration when compared with WT mice. Conversely, tumor-bearing Mpl-/- mice had reduced WBC counts, lymph node weights, and less liver infiltration than WT mice. Using an Mpl-deficient thrombocytopenic immunocompromised mouse model, our results were confirmed using the human non-Hodgkin lymphoma GRANTA cell line. Although we found that platelets and platelet-released molecules supported Emu-myc tumor cell survival in vitro, pharmacological inhibition of platelet function or anticoagulation in WT mice transplanted with Emu-myc 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 1 in TpoTg mice, whereas these levels were lower in Mpl-/- mice. Moreover, RNA sequencing of blood-resident Emu-myc lymphoma cells from TpoTg and WT mice after tumor transplantation revealed the upregulation of hallmark gene sets associated with an inflammatory response in TpoTg mice. We propose that the proinflammatory microenvironment in TpoTg mice promotes lymphoma progression.
- Publisher
- American Society of Hematology
- Keywords
- Mice; Animals; Humans; Megakaryocytes/metabolism; Receptors, Thrombopoietin; Blood Platelets/metabolism; *Thrombocytopenia/genetics; *Lymphoma/genetics; Tumor Microenvironment
- Department(s)
- Clinical Haematology
- PubMed ID
- 36075025
- Publisher's Version
- https://doi.org/10.1182/bloodadvances.2022007849
- Open Access at Publisher's Site
https://doi.org/10.1182/bloodadvances.2022007849- Terms of Use/Rights Notice
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Creation Date: 2023-07-18 07:52:28
Last Modified: 2023-07-18 07:52:55