Identification of deregulated mTORC1 signaling in advanced chronic myelogenous leukemia

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K21012
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology; Tumor therapeutics
• Research Institution: The University of Tokyo
• Principal Investigator: YOKOYAMA KAZUAKI 東京大学, 医科学研究所, 助教 (00647498)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 慢性骨髄性白血病 / チロシンキナーゼ阻害剤 / mTOR

Outline of Final Research Achievements

Despite the success with tyrosine kinase inhibitors (TKI) in most patients with chronic myelogenous leukemia (CML), some patients with advanced phase of CML still experience TKI resistance. Previous report indicated that Pi3K/mTOR signaling acted as a bypass signaling for survival when BCR/ABL is inhibited by TKI. However, the exact mechanism by which mTOR activation remains to be elucidated. To address this question, in this study we performed comparative RNA seq approach of tumor sample in advanced CML patients in comparison to those of patients with chronic phase. As a result, we found that an mTOR component was deregulated in advanced CML, which resulted in mTOR pathway deregulation. We are now performing in vitro experiment whether mTOR pathway deregulation could be induced by such deregulation of an mTOR componet.

Free Research Field

血液腫瘍学

Academic Significance and Societal Importance of the Research Achievements

慢性骨髄性白血病（CML）の原因であるBCRABLを阻害するチロシンキナーゼ阻害剤（TKI）は殆どの慢性期CML患者に長期生存をもたらしている。一方、進行期患者ではTKI耐性を示し、その予後は不良でありその克服が課題である。主な耐性機序の解明が必要である。申請者はmTOR経路が進行期CML症例においてBypass経路として働きTKI耐性に繋がっている事を、骨髄臨床検体を用いた網羅的な遺伝子発現解析にて見出した。特に、mTORの主要構成要素の遺伝子発現の制御異常が原因と考えられた。この脱制御機序の更なる解明は、mTOR経路を標的としたTKI耐性克服法開発に繋がる可能性を有している。