| Author |
Chen F, Zhao D, Xu Y, Zhang Y, Chen MH, Pathak KV, Hansen N, Lovell B, Liang Y, Estrella K, Wang WL, Ghoda L, Rockne R, Wu X, Ali H, Yu J, Caligiuri MA, Forman SJ, Trent JM, Kuo YH, Li L, Swiderski P, Zhang J, Kortylewski M, Nguyen LXT, Pirrotte P, Boldin M, Marcucci G, Zhang B.
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| 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.
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