FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N 6 -Methyladenosine RNA Demethylase

Abstract

SUMMARY N6-methyladenosine (m6A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m6A in cancer have been limited. Here we show that FTO, as an m6A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML). FTO is highly expressed in AMLs with t(11q23)/MLL-rearrangements, t(15;17)/PML-RARA, FLT3-ITD and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m6A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m6A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogensis and drug response.

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

“…In this study, Li et al. illustrated that FTO was significantly up‐regulated in certain sub‐types of AMLs such as MLL‐rearranged AML and acute promyelocytic leukaemia 61. Notable enrichment of FTO directly up‐regulated by the oncogenic proteins ( e.g .…”

“…Mechanistically, FTO exerted its oncogenic role by targeting the tumour suppressor ASB2 and RARA with its m 6 A demethylase catalytic activity. Thus, the FTO‐mediated inhibition of the ASB2/RARA axis with decreased overall m 6 A level markedly contributed to the carcinogenesis of AMLs 61. Recently, researchers have found the antileukaemic activity of R‐2HG, which was the production of mutant isocitrate dehydrogenase 1/2 and used to be considered as an oncometabolite, and FTO was involved in this progress.…”

The RNA code comes into focus

“…In the early 1970s, scientists first showed that mRNA was chemically modified by using radio isotope labelling of m 6 A. But because those studies enriched the mRNA transcripts by selecting their 3ʹ ends, which contain strings of adenosines, researchers worried that those preparations might contain trace amounts of other classes of RNA molecules, as well.…”

“…But because those studies enriched the mRNA transcripts by selecting their 3ʹ ends, which contain strings of adenosines, researchers worried that those preparations might contain trace amounts of other classes of RNA molecules, as well. "People stopped working on this because it was so difficult to get clear insights into whether the m 6 A in mRNA was a contaminant, " says Samie Jaffrey, a chemical biologist at Weill Cornell Medical College.…”

“…Also difficult was working out where in the transcriptome m 6 A was located, which could provide clues to its function. Conventional sequencing approaches involve reverse transcription -converting RNA into complementary DNA (cDNA), which is then amplified and sequenced.…”