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

Adv Sci (Weinh). 2021 Nov;8(22):e2100914. doi: 10.1002/advs.202100914. Epub 2021 Oct 5.

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.

Keywords: Wnt; acute myeloid leukemia; nuclear paraspeckle assembly transcript 1; translocation; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / metabolism
  • Cell Line, Tumor
  • Cell Self Renewal*
  • Cytoplasm / metabolism
  • Disease Models, Animal
  • Genes, Tumor Suppressor
  • Humans
  • Leukemia, Myeloid, Acute / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • RNA, Long Noncoding / metabolism*
  • Stem Cells
  • Wnt Signaling Pathway*

Substances

  • NEAT1 long non-coding RNA, human
  • RNA, Long Noncoding