Exploration of IKZF transcription factor complexes that induce immunomodulatory drugs (IMiDs) resistance.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08401
• 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: Osada Naoki 自治医科大学, 医学部, 助教 (60840858)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 多発性骨髄腫 / Lenalidomide耐性 / AP-１ファミリー / ChIP-Seq

Outline of Final Research Achievements

Lenalidomide (Len) plays an important role in the treatment of multiple myeloma. Clinically, resistance to Len is an urgent issue, but the mechanism of resistance remains unclear. In this study, we found that 1) c-Fos, a transcription factor of the activator protein-1 (AP-1) family, forms a complex with IKZF1 and activates transcription of genes essential for myeloma cell growth, and 2) residual c-Fos in the IKZF1 complex induces Len resistance. Furthermore, we show that the combination of AP-1 inhibitor and Len resulted in excellent growth inhibition and prolonged survival in vitro and in vivo.

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c-Fosは、AP-1ファミリー転写因子群(c-Fos/FosB/c-Jun/JunB/BATF)に属している。最近AP-1ファミリーは、多発性骨髄腫（MM）において多剤耐性獲得と再発にかかわっていることが次々と報告されている。本研究結果は、MMにおけるAP-1阻害剤の効果を明らかにした世界初の報告である。今後、新たな治療戦略の開発を介してMMの予後を改善する効果が期待できる。