Inhibition of LIN28B impairs leukemia cell growth and metabolism in acute myeloid leukemia

Abstract

BackgroundCurrent conventional chemotherapy for acute myeloid leukemia (AML) can achieve remission in over 70% of patients, but a majority of them will relapse within 5 years despite continued treatment. The relapse is postulated to be due to leukemia stem cells (LSCs), which are different from normal hematopoietic stem cells (HSCs). LIN28B is microRNA regulator and stem cell reprogramming factor. Overexpression of LIN28B has been associated with advance human malignancies and cancer stem cells (CSCs), including AML. However, the molecular mechanism by which LIN28B contributes to the development of AML remains largely elusive.MethodsWe modulated LIN28B expression in AML and non-leukemic cells and investigated functional consequences in cell proliferation, cell cycle, and colony-forming assays. We performed a microarray-based analysis for LIN28B-silencing cells and interrogated gene expression data with different bioinformatic tools. AML mouse xenograft model was used to examine the in vivo function of LIN28B.ResultsWe demonstrated that targeting LIN28B in AML cells resulted in cell cycle arrest, inhibition of cell proliferation and colony formation, which was induced by de-repression of let-7a miRNA. On the other hand, overexpression of LIN28B promoted cell proliferation. Data point to a mechanism where that inhibition of LIN28B induces metabolic changes in AML cells. IGF2BP1 was confirmed to be a novel downstream target of LIN28B via let-7 miRNA in AML. Notably, ectopic expression of LIN28B increased tumorigenicity, while silencing LIN28B led to slow tumor growth in vivo.ConclusionsIn sum, these results uncover a novel mechanism of an important regulatory signaling, LIN28B/let-7/IGF2BP1, in leukemogenesis and provide a rationale to target this pathway as effective therapeutic strategy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0507-y) contains supplementary material, which is available to authorized users.

Diverse roles of RNA‐binding proteins in cancer traits and their implications in gastrointestinal cancers

“…For example, LIN28A enhances translation of IGF2 by recruiting translation initiation complexes (Polesskaya et al, ). Some reports have shown that LIN28B functions as an oncogene in several cancers (Meder et al, ; Zhou et al, ). It has been shown in GC cells, that LIN28B directly binds to neuropilin‐1 (NRF‐1) 3′UTR and enhances its mRNA stability (X. Wang, Hu, et al, ).…”

NF-κB promotes the stem-like properties of leukemia cells by activation of LIN28B

“…We previously reported that human AML cell line TF-1a cells express abundant endogenous LIN28B protein[ 19 ]. In order to investigate the relationship between NF-κB and LIN28B, we treated the TF-1a cells with gradual concentrations of Bortezomib and MG-132, two different NF-κB inhibitors[ 20 ].…”

X‐linked inhibitor of apoptosis inhibition sensitizes acute myeloid leukemia cell response to TRAIL and chemotherapy through potentiated induction of proapoptotic machinery

“…The images were captured using Konica Medical SRX‐101A Medical Film Processor (Konica Minolta Medical & Graphic, Inc., Wayne, NJ, USA). Densitometric analysis was performed using Amersham Image Scanner with labscan imagequant tl Software (Amersham Biosciences, Piscataway, NJ, USA) (Zhou et al ., ). The protein levels of each molecule were normalized with each respective actin level.…”

“…IMAGEQUANT TL Software (Amersham Biosciences, Piscataway, NJ, USA) (Zhou et al, 2017). The protein levels of each molecule were normalized with each respective actin level.…”