Elucidation of the mechanisms of extramedullary disease development and drug resistance in multiple myeloma.

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08761
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Jichi Medical University
• Principal Investigator: Kikuchi Jiro 自治医科大学, 医学部, 准教授 (60371035)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 多発性骨髄腫 / 髄外増幅 / 薬剤耐性

Outline of Final Research Achievements

Elucidating the mechanism of extramedullary disease (EMD) development would contribute to improvement of treatment outcome in patients with MM. Here, we show that bone marrow stroma cell-derived hyaluronan (HA) elicits homophilic interactions of MM cells by binding to surface CD44 variants, under physiological shear stress and generates cell clusters that might develop into EMD. We recapitulated the development of EMD via administration of HA in a syngeneic murine MM model in a CD44-dependent manner. HA-induced MM cell clusters exhibited the specific resistance to proteasome inhibitors (PIs) via γ-secretase-mediated cleavage of the intracellular domains of CD44, which in turn transactivated PI resistance-inducible genes. Anti-CD44 antibody or γ-secretase inhibitors readily suppressed the development of EMD and significantly prolonged the survival of recipients. The HA-CD44 axis represents a novel pathway to trigger EMD development and could be a target of the treatment of EMD.

Free Research Field

血液学、腫瘍内科学

Academic Significance and Societal Importance of the Research Achievements

申請者が見出したシェアストレス下における骨髄腫細胞塊の形成は前例のない独自のモデルである。このモデルにより骨髄腫細胞同士の相互作用の役割や、薬剤耐性獲得における新たな機序解明の進展が期待できるなど、本研究には極めて高い学術的独創性が示唆される。また、髄外増幅発症と薬剤耐性獲得機序の解明は、その予防や克服に有効な新規治療法の開発を介して予後を改善する効果が期待できる。