Sakoda Teppei, Kikushige Yoshikane, Irifune Hidetoshi, Kawano Gentaro, Harada Takuya, Semba Yuichiro, Hayashi Masayasu, Shima Takahiro, Mori Yasuo, Eto Tetsuya, Kamimura Tomohiko, Iwasaki Hiromi, Ogawa Ryosuke, Yoshimoto Goichi, Kato Koji, Maeda Takahiro, Miyamoto Toshihiro, Akashi Koichi
Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan.
Cancer Sci. 2025 Mar;116(3):698-709. doi: 10.1111/cas.16431. Epub 2024 Dec 26.
In this study, we investigated the measurable residual leukemic stem cell (MR-LSC) population after allogeneic stem cell transplantation (allo-SCT) for high-risk acute myeloid leukemia (AML), utilizing T-cell immunoglobulin mucin-3 (TIM-3) expression as a functional marker of AML leukemic stem cells (LSCs). Analysis of the CD34CD38 fraction of bone marrow cells immediately after achievement of engraftment revealed the presence of both TIM-3LSCs and TIM-3 donor hematopoietic stem cells (HSCs) at varying ratios. Genetic analysis confirmed that TIM-3 cells harbored patient-specific mutations identical to those found in AML clones, whereas TIM-3 cells did not, indicating that TIM-3CD34CD38 cells represent residual AML LSCs. In 92 allo-SCT occasions involving 83 AML patients, we enumerated the frequencies of TIM-3LSCs immediately after achieving hematologic complete remission with complete donor cell chimerism. Notably, only 22.2% of patients who achieved a TIM-3MR-LSC status (<60%) experienced relapse, with a median event-free survival (EFS) of 1581 days (median follow-up duration was 2177 days among event-free survivors). Conversely, 87.5% of patients with TIM-3MR-LSC (≥60%) relapsed, with a median EFS of 140.5 days. Furthermore, MR-LSC status emerged as a significant independent risk factor for relapse (hazard ratio, 8.56; p < 0.0001), surpassing the impact of patient disease status prior to allo-SCT, including failure to achieve complete remission (hazard ratio, 1.98; p = 0.048). These findings suggest that evaluating TIM-3 MR-LSCs immediately after engraftment, which reflects the competitive reconstitution of residual TIM-3 LSCs and donor HSCs, may be valuable for predicting outcomes in AML patients undergoing allo-SCT.
在本研究中，我们利用T细胞免疫球蛋白粘蛋白-3（TIM-3）表达作为急性髓系白血病（AML）白血病干细胞（LSCs）的功能标志物，对高危急性髓系白血病患者进行异基因干细胞移植（allo-SCT）后的可测量残留白血病干细胞（MR-LSC）群体展开了研究。在植入成功后立即对骨髓细胞的CD34⁺CD38⁻部分进行分析，结果显示TIM-3⁺LSCs和TIM-3⁻供体造血干细胞（HSCs）以不同比例存在。基因分析证实，TIM-3⁺细胞携带与AML克隆中发现的相同的患者特异性突变，而TIM-3⁻细胞则没有，这表明TIM-3⁺CD34⁺CD38⁻细胞代表残留的AML LSCs。在涉及83例AML患者的92次allo-SCT病例中，我们在实现血液学完全缓解且供体细胞完全嵌合后立即对TIM-3⁺LSCs的频率进行了计数。值得注意的是，只有22.2%达到TIM-3⁺MR-LSC状态（<60%）的患者出现复发，无事件生存期（EFS）中位数为1581天（在无事件幸存者中，中位随访时间为2177天）。相反，87.5%的TIM-3⁺MR-LSC（≥60%）患者复发，EFS中位数为140.5天。此外，MR-LSC状态成为复发的一个显著独立危险因素（风险比，8.56；p<0.0001），超过了allo-SCT前患者疾病状态的影响，包括未实现完全缓解（风险比，1.98；p=0.048）。这些发现表明，在植入后立即评估TIM-3⁺MR-LSCs，这反映了残留TIM-3⁺LSCs和供体HSCs的竞争性重建，对于预测接受allo-SCT的AML患者的预后可能具有重要价值。
