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조회421

서울대학교병원

Haematologica, Jan 11 2024, | https://doi.org/10.3324/haematol.2023.283784 Elucidation of molecular basis of osteolytic bone lesions in advanced multiple myeloma

Dongyeop Shin^1,*, Myung-Jin Kim^2,*, Soyeon Chun^3,*, Dongchan Kim⁴, Chansu Lee⁵, Kwang-Sung Ahn⁶, Eunyoung Jung², Dayeon Kim², Byung-Chul Lee², Daehee Hwang^3,7,#, Yonghwan Kim^2,# and Sung-Soo Yoon^1,4,#

¹Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, South Korea

²Department of Biological Sciences, Research Institute of Women’s Health and Digital Humanity Center, Sookmyung Women’s University, Seoul 04310, South Korea

³School of Biological Sciences, Seoul National University, Seoul 08826, South Korea

⁴Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea

⁵Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea

⁶Functional Genome Institute, PDXen Biosystem Inc, Seoul 03080, South Korea

⁷Bioinformatics Institute, Seoul National University, Seoul 03080, South Korea

^*These authors equally contributed to this work.

^#Corresponding Authors : Yonghwan Kim, Ph.D., Daehee Hwang, Ph.D., Sung-Soo Yoon, M.D., Ph.D.

Abstract

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.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-12)
연구진국내 연구진
분야 생명과학 > 생화학

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