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<p>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.</p>

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miR-142 deficit in T cells during blast crisis promotes chronic myeloid leukemia immune escape

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月1日

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  • Fang Chen,
  • 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,
  • 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

摘要

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.