Specific ubiquitination and degradation through the proteasome system and development of the therapy resistance induced by mutated tyrosine kinase FLT3-ITD in AML

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17852
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Nogami Ayako 東京医科歯科大学, 医学部附属病院, 助教 (30754890)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: FLT3 / AML / ITD / proteasome / REDD1 / DUB / Rsk

Outline of Final Research Achievements

In the present study, we examine the responses of FLT3-ITD-transformed cells to
proteasome inhibitors and the molecular mechanisms underlying the responses. The results obtained shed light on mechanisms involved in apoptosis induced by bortezomib in FLT3-ITD-positive AML cells and suggest that the STAT5/Pim pathway and the downstream mTORC1/Mcl-1 pathway would provide promising targets to enhance the effectiveness of therapies with proteasome inhibitors against this type of AML with poor prognosis.　We also demonstrate that USP9x physically associates with FLT3-ITD and its inhibition leads to their downregulation by increasing K63-linked polyubiquitination and causing the aggresomal translocation to induce apoptosis efficiently in cells transformed by the mutants. It was further indicated that inhibition of USP9x may efficiently activate the mitochondrial apoptotic pathway cooperatively by inducing oxidative stress responses in addition to inhibition of FLT3-ITD signaling.

Free Research Field

造血器腫瘍

Academic Significance and Societal Importance of the Research Achievements

難治性のAMLの発症と進展に関わる恒常的活性化チロシンキナーゼ変異体を標的とした阻害薬は、治療抵抗性や耐性化が問題となる。特に、FLT3-ITD変異は全AMLの約30%を占め、標準的な治療には抵抗性かつ同種骨髄幹細胞移植を施しても予後不良であるが、他に手段が無く新たな治療戦略が待ち望まれる。本研究により解明した事実は、普遍的なタンパク分解機構を介した腫瘍の増殖機構という点では他分野にも外挿可能である点で学術的意義は高く、かつ、既存の化合物を用いた患者検体による評価により結論を導いており、治療戦略の実臨床への応用可能性が高い点で社会的に意義深い。