Deciphering the regulatory mechanism of autophagy by TXNIP in acute myeloid leukemia (AML)

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17875
• 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: Shubun University (2021); Tenri Health Care University (2019-2020)
• Principal Investigator: Noura Mina 修文大学, 医療科学部, 助手 (90828401)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: AML / TXNIP / オートファジー

Outline of Final Research Achievements

Various molecular-targeted drugs for cancer have been developed and are expected as effective therapeutic methods for acute myeloid leukemia (AML). The standard treatment for AML is chemotherapy with a combination of cytarabine and anthracycline; however, it often results in a poor prognosis due to the acquired resistance. This study tried to develop a new therapeutic strategy to overcome refractory AML. Using the clinical database, we revealed that downregulation of the tumor suppressor TXNIP is associated with a poor prognosis. Although the expression of TXNIP is suppressed in various cancers, its detailed molecular mechanism has not been elucidated. Here, we clarify the roles of TXNIP in AML and show the antitumor effect of combined treatment with TXNIP overexpression and Bcl-2 family protein inhibitor.

Free Research Field

細胞生物学、血液腫瘍学

Academic Significance and Societal Importance of the Research Achievements

TXNIPは様々な組織において腫瘍抑制に重要な役割を果たす。本研究では、MLL遺伝子再構成を伴うAMLにおいてTXNIPが細胞増殖を抑制し、オートファジーを誘導することを明らかにした。この成果は難治性MLL白血病の新規治療法の開発に寄与する。また本研究ではTXNIPの過剰発現が既存のBcl-2ファミリー阻害薬であるABT-263のアポトーシス誘導作用を増強することを明らかにした。この成果はTXNIPによるオートファジー誘導がアポトーシスに与える影響について新たな知見をもたらし、オートファジーとアポトーシスのクロストークを制御する革新的治療法の確立につながると展望する。