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Sci Transl Med. 2019 May 29;11(494). pii: eaau9087. doi: 10.1126/scitranslmed.aau9087.

Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease.

Author information

1
Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
3
Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China.
4
Department of Pathophysiology, Tianjin Medical University, Tianjin, People's Republic of China.
5
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
9
Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA.
10
Department of Hematology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 160 Pujian Rd, Shanghai, People's Republic of China.
11
Cancer Center for Hematological Malignancies, Houston Methodist Hospital, Houston, TX 77030, USA.
12
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
13
Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. jiyang@mdanderson.org.

Abstract

Osteolytic lesions in multiple myeloma are caused by osteoclast-mediated bone resorption and reduced bone formation. A unique feature of myeloma is a failure of bone healing after successful treatment. We observed adipocytes on trabecular bone near the resorbed area in successfully treated patients. Normal marrow adipocytes, when cocultured with myeloma cells, were reprogrammed and produced adipokines that activate osteoclastogenesis and suppress osteoblastogenesis. These adipocytes have reduced expression of peroxisome proliferator-activated receptor γ (PPARγ) mediated by recruitment of polycomb repressive complex 2 (PRC2), which modifies PPARγ promoter methylation at trimethyl lysine-27 histone H3. We confirmed the importance of methylation in the PPARγ promoter by demonstrating that adipocyte-specific knockout of EZH2, a member of the PRC2, prevents adipocyte reprogramming and reverses bone changes in a mouse model. We validated the strong correlation between the frequency of bone lesions and the expression of EZH2 in marrow adipocytes from patients in remission. These results define a role for adipocytes in genesis of myeloma-associated bone disease and that reversal of adipocyte reprogramming has therapeutic implications.

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