miR-142 deficit in T cells during blast crisis promotes chronic myeloid leukemia immune escape
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.
Authors
- Xiwei Wu
- Marcin Kortylewski (ORCID: https://orcid.org/0000-0002-6003-1816)
- Wei-Le Wang (ORCID: https://orcid.org/0000-0002-6984-4514)
- Mark Boldin (ORCID: https://orcid.org/0000-0003-4593-0669)
- Dandan Zhao (ORCID: https://orcid.org/0000-0001-5194-750X)
- Russell C. Rockne (ORCID: https://orcid.org/0000-0002-1557-159X)
- Ya‐Huei Kuo (ORCID: https://orcid.org/0000-0003-2595-0419)
- Jeffrey M. Trent (ORCID: https://orcid.org/0000-0003-0183-4202)
- Le Xuan Truong Nguyen (ORCID: https://orcid.org/0000-0001-5464-0861)
- Stephen J. Forman (ORCID: https://orcid.org/0000-0002-2803-4152)
- Fang Chen (ORCID: https://orcid.org/0000-0002-7616-7224)
- Piotr Swiderski
- Michael A. Caligiuri (ORCID: https://orcid.org/0000-0002-4095-3020)
- Lucy Ghoda (ORCID: https://orcid.org/0000-0002-8212-3586)
- Nancy F. Hansen (ORCID: https://orcid.org/0000-0002-0950-0699)
- Min-Hsuan Chen
- Guido Marcucci (ORCID: https://orcid.org/0000-0002-3983-5908)
- Jianhua Yu (ORCID: https://orcid.org/0000-0002-0326-3223)
- Haris Ali (ORCID: https://orcid.org/0000-0002-9728-7292)
- Patrick Pirrotte (ORCID: https://orcid.org/0000-0003-1360-6039)
- Khyatiben V. Pathak (ORCID: https://orcid.org/0000-0002-8050-0747)
- Yong H. Liang (ORCID: https://orcid.org/0000-0002-7225-7062)
- Katrina Estrella (ORCID: https://orcid.org/0009-0003-0418-8741)
- Yi Zhang (ORCID: https://orcid.org/0000-0003-3419-2461)
- Bin Zhang (ORCID: https://orcid.org/0000-0003-4703-7524)
- Ling Li (ORCID: https://orcid.org/0000-0001-7568-939X)
- Jianying Zhang (ORCID: https://orcid.org/0000-0001-6552-2617)
- Brooke Lovell (ORCID: https://orcid.org/0009-0008-1023-2186)
- Yongfang Xu
Institutions
- Translational Genomics Research Institute (US)
- City Of Hope National Medical Center (US)
- City of Hope (US)
- First Affiliated Hospital Zhejiang University (CN)
- Beckman Research Institute
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1038/s41467-025-56383-y
- Citations
- 3
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 2.39
Funders
- Comprehensive Cancer Center, City of Hope
- National Institutes of Health
- National Cancer Institute