Advanced Science, 5 October, 2021, DOI：https://doi.org/10.1002/advs.202100914

Cytoplasmic NEAT1 Suppresses AML Stem Cell Self-Renewal and Leukemogenesis through Inactivation of Wnt Signaling

Huiwen Yan, Zhi Wang, Yao Sun, Liangding Hu, Pengcheng Bu

Abstract

As an essential component of paraspeckles, nuclear paraspeckle assembly transcript 1 (NEAT1) localizes in the nucleus, promoting progression of various malignant solid tumors. Herein, an adverse effect of NEAT1 is reported, showing that the short isoform, NEAT1_1 suppresses acute myeloid leukemia (AML) development. NEAT1_1 is downregulated in leukemia stem cells (LSCs) and its decreased expression correlates with recurrence in AML patients. It is demonstrated that NEAT1_1 suppresses leukemogenesis and LSC function but is dispensable for normal hematopoiesis. Mechanistically, NEAT1_1 is released from the nucleus into the cytoplasm of AML cells, regulated by transcription factor C/EBPβ and nuclear protein NAP1L1. Cytoplasmic NEAT1_1 interacts with Wnt component DVL2 and E3 ubiquitin ligase Trim56, facilitates Trim56-mediated DVL2 degradation, and thus suppresses Wnt signaling. Collectively, the findings show NEAT1_1 is translocated from the nucleus to the cytoplasm and acts as a tumor suppressor in AML.

Article link：https://onlinelibrary.wiley.com/doi/10.1002/advs.202100914