Page 193 - Haematologica Vol. 109 - July 2024

ARTICLE - Plasma Cell Disorders
Elucidation of molecular basis of osteolytic bone lesions in
advanced multiple myeloma
Dongyeop Shin,1* Myung-Jin Kim,2* Soyeon Chun,3* Dongchan Kim,4 Chansu Lee,5 Kwang-Sung Ahn,6 Eunyoung Jung,2 Dayeon Kim,2 Byung-Chul Lee,2 Daehee Hwang,3,7 Yonghwan Kim2 and Sung-Soo Yoon1,4
1Department of Internal Medicine, Seoul National University Hospital; 2Department of Biological Sciences, Research Institute of Women’s Health and Digital Humanity Center, Sookmyung Women’s University; 3School of Biological Sciences, Seoul National University; 4Cancer Research Institute, Seoul National University College of Medicine; 5Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine; 6Functional Genome Institute, PDXen Biosystem Inc. and 7Bioinformatics Institute, Seoul National University, Seoul, South Korea
*DS, M-JK and SC contributed equally as first authors.
Abstract
Osteolytic bone lesion is a major cause of lower 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 (BM) 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 BM-derived plasma and found to be significantly higher in MM than in AML or ALL, which 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 b-catenin. These results collectively show that the 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 the osteolytic process in MM with hyperdiploidy.
Correspondence: Y. Kim yhkim@sookmyung.ac.kr
D. Hwang
daehee@snu.ac.kr
Sung-Soo Yoon
ssysmc@snu.ac.kr
Received: Accepted: Early view:
June 19, 2023. January 2, 2024. January 11, 2024.
https://doi.org/10.3324/haematol.2023.283784
©2024 Ferrata Storti Foundation Published under a CC BY-NC license
Introduction
Multiple myeloma (MM) is the second most common he- matologic malignancy involving malignant plasma cells. MM is characterized by the presence of clonal plasma cells producing fragmented monoclonal immunoglobulins of var- ious heavy and light chain subtypes. In the US, the overall 5-year survival rate for patients with MM is 55%,1,2 despite combination chemotherapy with potent target agents, and even high-dose chemotherapy and autologous hematopoietic stem cell transplantation. MM causes various complications, including osteolytic bone lesion, anemia, renal failure, hy- percalcemia, and hyperviscosity syndrome.3
Osteolytic bone lesions at multiple sites are a unique fea- ture of MM, which differs from other hematologic cancers
such as acute and chronic leukemia or lymphoma. The chief complaint in about two-thirds of MM patients is bone pain due to the direct bone involvement of myeloma tumor cells or indirect effect of myeloma tumor cells or tumor microenvironment-secreting cytokines on bony skeleton. Skeletal-related events (SRE) in MM patients include in- tractable bone pain, fracture, and paralysis due to spinal cord compression,4 which radically lower patients’ quality of life (QoL) and place a substantial burden on healthcare resources.5,6 Recent advances in treatment for MM have re- markably improved the median overall survival of patients with MM up to over 5 years.7 Accordingly, QoL has become a more important issue for long-term MM survivors. Further- more, bone osteolysis has a negative impact on the survival of MM.8 Osteolytic bone lesions, a major cause of morbidity
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