Chen Fang, Zhao Dandan, Xu Yongfang, Zhang Yi, Chen Min-Hsuan, Pathak Khyatiben V, Hansen Nate, Lovell Brooke, Liang Yong, Estrella Katrina, Wang Wei-Le, Ghoda Lucy, Rockne Russell, Wu Xiwei, Ali Haris, Yu Jianhua, Caligiuri Michael A, Forman Stephen J, Trent Jeff M, Kuo Ya-Huei, Li Ling, Swiderski Piotr, Zhang Jianying, Kortylewski Marcin, Nguyen Le Xuan Truong, Pirrotte Patrick, Boldin Mark, Marcucci Guido, Zhang Bin
Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA.
Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.
Nat Commun. 2025 Feb 1;16(1):1253. doi: 10.1038/s41467-025-56383-y.
We reported that an acquired miR-142 deficit transforms chronic phase (CP) chronic myeloid leukemia (CML) leukemic stem cells (LSCs) into blast crisis (BC) LSCs. Given the role of miR-142 in the development and activity of the immune system, we postulated that this deficit also promotes LSC immune escape. Herein, we report on IL-6-driven miR-142 deficit occurring in T cells during BC transformation. In CML murine models, miR-142 deficit impairs thymic differentiation of lymphoid-primed multipotent progenitors (LMPP) into T cells and prevents T cells' metabolic reprogramming, thereby leading to loss of T cells and leukemia immune escape. Correcting miR-142 deficit with a miR-142 mimic compound (M-miR-142), alone or in combination with immune checkpoint antibodies, restores T cell number and immune activity, leading to LSC elimination and prolonged survival of BC CML murine and patient-derived xenograft models. These observations may open new therapeutic opportunities for BC CML and other myeloid malignancies.
我们曾报道，获得性miR-142缺陷可将慢性期（CP）慢性髓系白血病（CML）白血病干细胞（LSC）转变为急变期（BC）LSC。鉴于miR-142在免疫系统发育和活性中的作用，我们推测这种缺陷也会促进LSC免疫逃逸。在此，我们报告了BC转化过程中T细胞中由白细胞介素-6（IL-6）驱动的miR-142缺陷。在CML小鼠模型中，miR-142缺陷会损害淋巴系多能祖细胞（LMPP）向T细胞的胸腺分化，并阻止T细胞的代谢重编程，从而导致T细胞丢失和白血病免疫逃逸。用miR-142模拟化合物（M-miR-142）单独或与免疫检查点抗体联合纠正miR-142缺陷，可恢复T细胞数量和免疫活性，导致LSC清除，并延长BC CML小鼠模型和患者来源异种移植模型的生存期。这些观察结果可能为BC CML和其他髓系恶性肿瘤带来新的治疗机会。
