Cytoplasmic NEAT1 Suppresses AML Stem Cell Self-Renewal and Leukemogenesis through Inactivation of Wnt Signaling.
Huiwen YanZhi WangYao SunLiangding HuPengcheng BuPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2021)
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.
Keyphrases
- acute myeloid leukemia
- stem cells
- allogeneic hematopoietic stem cell transplantation
- signaling pathway
- transcription factor
- induced apoptosis
- end stage renal disease
- ejection fraction
- poor prognosis
- emergency department
- binding protein
- mesenchymal stem cells
- cell proliferation
- cell therapy
- endoplasmic reticulum stress
- oxidative stress
- peritoneal dialysis
- protein protein
- dna binding