Elucidation of molecular basis of osteolytic bone lesions in advanced multiple myeloma
Dongyeop Shin,
Myung-Jin Kim,
Soyeon Chun,
Dongchan Kim,
Chansu Lee,
Kwang-Sung Ahn,
Eunyoung Jung,
Dayeon Kim,
Byung-Chul Lee,
Daehee Hwang,
Yonghwan Kim,
Sung-Soo Yoon
Affiliations
Dongyeop Shin
Department of Internal Medicine, Seoul National University Hospital, Seoul 03080
Myung-Jin Kim
Department of Biological Sciences, Research Institute of Women’s Health and Digital Humanity Center, Sookmyung Women’s University, Seoul 04310
Soyeon Chun
School of Biological Sciences, Seoul National University, Seoul 08826
Dongchan Kim
Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080
Chansu Lee
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351
Kwang-Sung Ahn
Functional Genome Institute, PDXen Biosystem Inc, Seoul 03080
Eunyoung Jung
Department of Biological Sciences, Research Institute of Women’s Health and Digital Humanity Center, Sookmyung Women’s University, Seoul 04310
Dayeon Kim
Department of Biological Sciences, Research Institute of Women’s Health and Digital Humanity Center, Sookmyung Women’s University, Seoul 04310
Byung-Chul Lee
Department of Biological Sciences, Research Institute of Women’s Health and Digital Humanity Center, Sookmyung Women’s University, Seoul 04310
Daehee Hwang
School of Biological Sciences, Seoul National University, Seoul 08826, South Korea; Bioinformatics Institute, Seoul National University, Seoul 03080
Yonghwan Kim
Department of Biological Sciences, Research Institute of Women’s Health and Digital Humanity Center, Sookmyung Women’s University, Seoul 04310
Sung-Soo Yoon
Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, South Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080
Osteolytic bone lesion is a major cause of decreased quality of life and poor prognosis in patients with multiple myeloma (MM), but molecular pathogenesis of the osteolytic process in MM remains elusive. Fms-like tyrosine kinase 3 ligand (FLT3L) was reported to be elevated in bone marrow and blood of patients with advanced MM who often show osteolysis. Here, we investigated a functional link of FLT3L to osteolytic process in MM. We recruited 86, 306 and 52 patients with MM, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), respectively. FLT3L levels of patients with hematologic malignancies were measured in bone marrow-derived plasma and found to be significantly elevated in MM than in AML or ALL that rarely show osteolysis. FLT3L levels were further elevated in MM patients with bone lesion compared with patients without bone lesion. In vitro cell-based assays showed that the administration of FLT3L to HEK293T, HeLa and U2OS cells led to an increase in the DKK1 transcript level through STAT3 phosphorylation at tyrosine 705. WNT reporter assay showed that FLT3L treatment reduced WNT signaling, and nuclear translocation of β-catenin. These results collectively show that FLT3L-STAT3-DKK1 pathway inhibits WNT signaling-mediated bone formation in MM, which can cause osteolytic bone lesion. Finally, transcriptomic profiles revealed that FLT3L and DKK1 were predominantly elevated in the hyperdiploidy subtype of MM. Taken together, FLT3L can serve as a promising biomarker for predicting osteolytic bone lesion and also a potential therapeutic target to prohibit the progression of osteolytic process in MM with hyperdiploidy.
