novel endogenous mechanizm against leukemogenesis in ABL family oncogene.

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08368
• 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: Kyoto Prefectural University of Medicine
• Principal Investigator: OKUDA KEIKO 京都府立医科大学, 医学(系)研究科(研究院), 助教 (70305572)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ABL ファミリー遺伝子 / 造血器腫瘍 / 発がんシグナル / 白血病 / Mastcytosis / 発がん制御

Outline of Final Research Achievements

ARG (ABL2) is highly homologous to ABL (ABL1), and the chimeric TEL/ABL and TEL/ARG have been identified in leukemia patients. In previous study, TEL/ABL and TEL/ARG induce the specific disease in mice, that is early onset myeloid leukemia and long-latency mastocytosis, respectively.
To determine the molecular mechanisms on their distinct biological properties, a series of mutants of TEL/ARG were generated. The difference in cell proliferative activity was caused by the restraint action of ARG-C terminus and located specific proline and tyrosine residue was considered to participate for the function. ARG-N terminus, where the specific binding to STAT3 was observed by Yeast Two Hybrid system, might have a role in mast cell development. These findings suggest that specific site in ARG C-terminus is responsible for cell proliferation reflecting the disease latency, and specific isoform of STAT may influences on differentiation of hematopoietic cells reflecting the disease phenotype.

Free Research Field

血液腫瘍学、細胞生物学

Academic Significance and Societal Importance of the Research Achievements

今回得た基礎結果をさらに発展させて造白血病活性を制御する新たな内因性メカニズムの特定を目指しており,その理解により新規分子標的治療法の開発に繋がることが期待できる.
また Mastocytosis の病因として新たにARG の関与を提言できたことは, 今後の診断や治療選択への有用性から臨床に大きく貢献できる. 病態方向性の違いを通して, 基礎的にはABLファミリー遺伝子間での血球分化誘導における役割や, 特異的機能発現に関わる転写因子STATアイソフォーム使い分けの理解に役立つと期待される.