Bone marrow adipocytes fuel myeloma: phenotype and lipid profiling in MGUS and multiple myeloma — ASN Events
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  3. Bone marrow adipocytes fuel myeloma: phenotype and lipid profiling in MGUS and multiple myeloma

Bone marrow adipocytes fuel myeloma: phenotype and lipid profiling in MGUS and multiple myeloma (#103)

Melissa D Cantley 1 2 , Laura J Trainor 1 2 , Mackenzie Skinner 1 2 , Marten Snel 3 , Andrew CW Zannettino 1 2 , Paul J Trim 3 , Kate Vandyke 1 2
  1. Myeloma Research Laboratory, School of Pharmacy and Biomedical Science, Adelaide University, Adelaide, South Australia, Australia
  2. Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
  3. Metabolomics and MS-Imaging Core Facility, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

Background/aim: Bone marrow (BM) adipocytes (BMADs) make up to 70% of the BM microenvironment and support multiple myeloma (MM) plasma cell (PC) proliferation. However, it remains unclear whether MM development is associated with changes to the BMAD phenotype contributing to a MM supportive microenvironment. This study aimed to assess BMAD phenotypes in MM patients, compared with the precancerous stage monoclonal gammopathy of undetermined significance (MGUS).

Methods: BMAD quantitation was conducted on H&E-stained trephine biopsies from newly diagnosed MGUS (n=9) and MM (n=14). Mesenchymal stromal cells (MSCs) from MGUS (n=14) and MM (n=14) trephines were cultured in adipogenic media and 1) stained with Nile Red/DAPI to quantitate adipocyte number and lipid droplets/adipocyte 2) lipids extracted and quantitated by liquid-chromatography mass spectrometry (LC-MS) and 3) cocultured with MMPC lines (RPMI-8226 and U266) to assess effects on proliferation, compared with monoculture.

Results: Histomorphometric analysis revealed no significant difference in the number of adipocytes per mm2 of marrow area between MM and MGUS. MM patients with larger mean BMAD size (>2100µm2) had significantly poorer overall survival, compared with patients with smaller BMADs (median survival:113 and 231 weeks; p=0.045, log-rank test). In vitro analysis revealed a 2-fold reduction in adipocyte number (p=0.039) and a 2.6-fold reduction in the number of lipid droplets/adipocyte (p=0.0005) in MM compared with MGUS. Lipidomic analysis revealed altered levels of lipid classes including phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol and sphingolipids in MM compared with MGUS adipocytes. Furthermore, in vitro adipocyte cultures from MM patients demonstrated an increased capacity to support human MMPC proliferation (RPMI-8226: p=0.0286; U266: p=0.0148) in vitro, compared with MGUS adipocytes.

Conclusions: Histomorphometric analyses revealed an association between BMAD phenotype and myeloma outcomes. In vitro analysis demonstrated an altered adipocyte phenotype suggesting MM may be associated with remodelling of the adipocyte microenvironment in the BM. Notably, this was associated with increased capacity to support MMPC proliferation in co-cultures. Future studies will investigate how MM adipocyte-derived lipid species affect MMPC proliferation. Furthermore, spatial lipidomic analysis will investigate adipocyte phenotypes in situ in the BM and how this is associated with adipocyte size, to better understand how specific adipocyte populations support MMPCs.