The mRNA demethylase FTO promotes leukemogenesis and inhibits ATRA-mediated differentiation.
Major finding: The mRNA demethylase FTO promotes leukemogenesis and inhibits ATRA-mediated differentiation.
Mechanism: FTO demethylates m6A sites in the 3′-UTRs of ASB2 and RARA to decrease ASB2 and RARA mRNA stability.
Impact: Targeting FTO may be a potential therapy, alone or in combination with ATRA, for patients with AML.
N6-methyladenosine (m6A) methylation is the most common type of mRNA modification and may impact biological regulation analogous to the well-studied reversible DNA and histone modifications. FTO, the first RNA demethylase to be identified, is associated with increased body mass and obesity, but its role in oncogenesis has not been investigated. To determine the impact of FTO in tumorigenesis, Li and colleagues interrogated the role of FTO in acute myeloid leukemia (AML). FTO was shown to be highly overexpressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations, all of which directly upregulated expression of FTO. Overexpression of FTO resulted in decreased global m6A levels and increased cell growth, resistance to apoptosis, and transformation; similarly, knockdown of FTO in these leukemia cell lines resulted in the opposite phenotype. Further, FTO overexpression accelerated leukemogenesis, whereas FTO knockdown delayed the onset of AML, in mouse bone marrow transplantation assays. Simultaneous m6A and RNA sequencing of FTO-overexpressing and control AML cell lines identified genes potentially regulated by FTO; among these, ankyrin repeat and SOCS box containing 2 (ASB2) and retinoic acid receptor alpha (RARA) were significantly hypomethylated and downregulated in FTO-overexpressing cells. Similarly, expression of ASB2 and RARA was inversely correlated to FTO expression in human AML cohorts, and expression or ablation of FTO expression resulted in, respectively, ablation or expression of ASB2 and RARA; knockdown of ASB2 or RARA promoted AML cell growth and viability and rescued the antileukemogenic effects of FTO knockdown. Further, FTO was shown to negatively regulate the stability of ASB2 and RARA transcripts via m6A sites in the ASB2 and RARA 3′-UTRs, and expression of FTO inhibited all-trans retinoic acid (ATRA)–mediated differentiation of AML cells. Together, these findings elucidate the role of FTO in leukemogenesis and suggest that inhibition of FTO, particularly in combination with ATRA, may be a potential therapy for patients with FTO-overexpressing AMLs.