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Runx2 Deficiency in Osteoblasts Promotes Myeloma Progression by Altering the Bone Microenvironment at New Bone Sites
Xiaoxuan Xu1,2, Chao Zhang1,2, Timothy N Trotter2
1Department of Hematology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Cancer Research
|January 9, 2020
Summary
Multiple myeloma bone marrow immunity is suppressed when osteoblast Runt-related transcription factor 2 (Runx2) is deficient. This deficiency attracts cancer cells and promotes tumor growth, but myeloid-derived suppressor cell depletion can block progression.
Area of Science:
- Bone Biology
- Cancer Immunology
- Myeloma Pathogenesis
Background:
- Multiple myeloma (MM) cells disseminate to new bone sites before detectable metastasis.
- MM cells suppress osteoblastogenesis via Runt-related transcription factor 2 (Runx2) inhibition in immature osteoblasts (OB).
- The feedback loop between OB-Runx2 suppression and MM progression is unknown.
Purpose of the Study:
- To investigate the effect of OB-Runx2 deficiency on MM dissemination and progression.
- To elucidate the mechanisms by which OB-Runx2 deficiency impacts the bone marrow microenvironment.
- To determine if targeting myeloid-derived suppressor cells (MDSCs) can impede MM progression in this model.
Main Methods:
- Developed a syngeneic mouse model with Runx2 specifically deleted in immature osteoblasts (OB-Runx2-/- mice).
- Utilized *in vivo* studies to assess MM cell attraction and tumor growth in OB-Runx2-/- mice.
- Conducted mechanistic studies to analyze the bone marrow microenvironment, including immune cell populations and cytokine profiles.
- Administered gemcitabine or 5-fluorouracil to deplete MDSCs and evaluate their impact on MM progression.
Main Results:
- OB-Runx2 deficiency significantly attracted MM cells and promoted tumor growth in the bone marrow.
- OB-Runx2 deficiency created an immunosuppressive bone marrow microenvironment characterized by increased MDSCs and suppressed cytotoxic CD8+ T cells.
- MDSC depletion using gemcitabine or 5-fluorouracil effectively inhibited MM tumor growth in OB-Runx2-/- mice.
- OB-Runx2 deficiency increased metastatic cytokines and MDSCs, while suppressing bone marrow immunity.
Conclusions:
- Osteoblast Runx2 deficiency in new bone sites promotes multiple myeloma dissemination and progression.
- This progression is mediated by increased metastatic cytokines and MDSCs, alongside suppressed bone marrow immunity.
- Depletion of MDSCs represents a potential therapeutic strategy to counteract MM progression driven by OB-Runx2 deficiency.
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