Exploration of Predictive Biomarkers for Combined BCL2 and Methylation Inhibitor Therapies in Elderly Leukemia Patients

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K20913
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Juntendo University
• Principal Investigator: YAMATANI KOTOKO 順天堂大学, 医学部, 非常勤助教 (90909805)
• Project Period (FY): 2021-08-30 – 2024-03-31
• Keywords: 急性骨髄性白血病 / ベネトクラクス / デシタビン / 治療抵抗性

Outline of Final Research Achievements

The combination of venetoclax (VEN), an inhibitor of the anti-apoptotic factor BCL2, with the hypomethylating agent, decitabine (DEC) is the current frontline standard of care for elderly patients with acute myeloid leukemia (AML). Despite the success of VEN/DEC in inducing remission in AML, a significant proportion of patients remain refractory to combination therapy. Our RNA sequencing analysis revealed that genes related to fatty acid metabolism were significantly upregulated in leukemia cells obtained from non-responders after treatment with VEN/DEC. We identified significantly increased expression of Peroxisome Proliferator-Activated Receptor gamma (PPARG) in these non-responders after treatment. Furthermore, AML cells overexpressing PPARG acquired VEN/DEC resistance with up-regulation of fatty acid metabolism. These findings suggest that elevated PPARG expression affects cellular energy metabolism and contributes to treatment resistance.

Free Research Field

臨床検査医学

Academic Significance and Societal Importance of the Research Achievements

本研究は、高齢者白血病に対するベネトクラクスとデシタビン併用療法の治療抵抗性の分子機構を解明し、がん治療における新たな知見を提供する。PPARGを含むエネルギー代謝に関与する遺伝子発現パターンを識別マーカーとして利用することで、個別化医療に応用できる可能性を示唆する。さらに、PPARGおよび脂肪酸代謝経路が治療抵抗性に関与することを示し、新たな治療標的を提案する。本研究は、治療効果を最大化し、患者の生存率と生活の質を向上させ、医療コストの削減にも寄与し、がん治療の選択肢を広げる基盤を提供する。