LEF1‐AS1, long non‐coding RNA, inhibits proliferation in myeloid malignancy

LEF1 antisense RNA 1 (LEF1‐AS1) is an antisense long non‐coding RNA encoded in the lymphoid enhancer‐binding factor 1 (LEF1) locus. LEF1‐AS1 is a conserved transcript dysregulated in hematopoiesis. This study aimed to functionally characterize the role of this transcript in myeloid malignancy and explore a possible regulatory effect of LEF1‐AS1 upon LEF1. We show that LEF1‐AS1 is highly expressed in normal hematopoietic stem cells but barely detectable in myeloid malignant cell lines. Additionally, bone marrow cells from myelodysplastic syndrome (n=12) and acute myeloid malignancy patients (n=28) expressed significantly reduced levels of LEF1‐AS1 compared to healthy controls (n=15). Artificial LEF1‐AS1 over‐expression inhibited proliferation in HL60 and led to an upregulation of tumor suppressors p21 and p27, and reduced ERK1/2 activation. Unexpectedly, no underlying modulation of LEF1 was detected. Ectopic expression of LEF1‐AS1 also inhibited proliferation in HELA, a cell line lacking endogenous expression of LEF1, supporting a LEF1‐independent mechanism. Additionally, transient over‐expression of LEF1‐AS1 in AML patient cells also led to reduced proliferation and colony formation capacity. We used a mass spectrometry‐based proteomics approach. Proteomic quantification identified the modulation of an important metabolic regulator, Fumarase, and concomitant accumulation of the metabolite fumarate.