miR-142 deficit in T cells during blast crisis promotes chronic myeloid leukemia immune escape
Abstract
Abstract 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.
Article Details
Authors (29)
Fang Chen
Hefei National Research Center for Physical Sciences at the Microscale, Department of Materials Science and Engineering
Dandan Zhao
Yongfang Xu
Yi Zhang
Min-Hsuan Chen
Khyatiben V. Pathak
Nate Hansen
Brooke Lovell
Yong Liang
Katrina Estrella
Wei-Le Wang
Lucy Ghoda
Russell Rockne
Xiwei Wu
Haris Ali
Jianhua Yu
Michael A. Caligiuri
Stephen J. Forman
City of Hope National Medical Center, Duarte, CA
Jeff M. Trent
Ya-Huei Kuo
Ling Li
Piotr Swiderski
Jianying Zhang
Marcin Kortylewski
Le Xuan Truong Nguyen
Patrick Pirrotte
Mark Boldin
Guido Marcucci
Bin Zhang