Introduction:

Acute myeloid leukemia (AML) is a biologically heterogeneous, malignant disease of the hematopoietic system. In ~10% of AML cases, the full- length isoform (p42) of the transcription factor CCAAT/enhancer binding protein alpha (C/EBPα), an essential regulator of granulopoiesis, is mutated. N-terminal mutations shift expression towards the truncated C/EBPα isoform (p30), promoting proliferation of leukaemic blasts. The self-renewal ability of AML cells can be suppressed by the short isoform of the long non-coding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1.1). This study investigated whether C/EBPα-p42 or the “mutated” p30 isoforms directly regulate NEAT1.1 or the long isoform NEAT1.2 during differentiation.

Material and methods:

In 184 de novo AML patients with wild-type CEBPA and 13 de novo AML patients with mutated CEBPA from the TCGA database, expression of lncRNA NEAT1 was analyzed. In vitro, a K562-based cell model for inducible granulopoietic differentiation of the isoforms C/EBPα-p42 and C/EBPα-p30 was used to investigate the regulation of NEAT1.1 or NEAT1.2 using qRT-PCR.

Results:

NEAT1 shows significantly higher expression in wild-type CEBPA patients than in mutated CEBPA patients. In vitro, after 24 h of differentiation induced by translocation of the C/EBPα-p42 isoform from the cytoplasm into the nucleus, the expression of lncRNA NEAT1.1 is upregulated 2.15-fold. For the C/EBPα p30 isoform, NEAT1.1 expression is upregulated 1.59- fold. NEAT1.2 was not significantly regulated.

Conclusions:

NEAT1.1 is regulated by C/EBPα in AML. Consequently, a mutation in the CEBPA gene not only influences direct targets in gene regulation but also affects targets regulated by NEAT1.1.