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FTO depletion does not alter m6A stoichiometry in AML mRNA: a reassessment using direct RNA nanopore sequencing (Direct-RNA Nanopore-seq data)

ABSTRACT: The RNA demethylase FTO has been proposed to promote acute myeloid leukemia (AML) by demethylating N6-methyladenosine (m6A) from oncogenic transcripts such as MYC. However, these studies relied on methods that are non-quantitative and unable to reveal m6A stoichiometry changes before or after FTO depletion. To directly test whether FTO regulates m6A in mRNA, we employed Oxford Nanopore direct RNA sequencing to map and quantify m6A at single-nucleotide resolution. We observed that across the transcriptome and at MYC-specific sites, m6A stoichiometry remained stable despite depletion of FTO activity by knockout, knockdown, or pharmacologic inhibition. This pattern was seen in AML cell lines MONOMA-6 and MOLM-13, as well as in the non-AML cell line HEK293T. Moreover, we do not find an essential oncogenic role for FTO in AML cells lines. Instead, we find that FTO depletion does not impair AML cell viability, and the small-molecule FTO inhibitor FB23-2 is cytotoxic even in FTO-deficient cells, indicating that its toxicity occurs through an FTO-independent mechanism of action. In contrast, FTO depletion caused a robust increase in N6,2’-O-dimethyladenosine (m6Am) in snRNAs, consistent with m6Am being a target of FTO. Together, these findings argue against the model that FTO functions as an “m6A eraser” in AML and caution against attributing the effects of FTO depletion and FTO inhibitors to decreased m6A demethylation.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE311653 | GEO | 2025/12/31

REPOSITORIES: GEO

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FTO depletion does not alter m6A stoichiometry in AML mRNA: a reassessment using direct RNA nanopore sequencing (GLORI data)

Project description:The RNA demethylase FTO has been proposed to promote acute myeloid leukemia (AML) by demethylating N6-methyladenosine (m6A) from oncogenic transcripts such as MYC. However, these studies relied on methods that are non-quantitative and unable to reveal m6A stoichiometry changes before or after FTO depletion. To directly test whether FTO regulates m6A in mRNA, we employed Oxford Nanopore direct RNA sequencing to map and quantify m6A at single-nucleotide resolution. We observed that across the transcriptome and at MYC-specific sites, m6A stoichiometry remained stable despite depletion of FTO activity by knockout, knockdown, or pharmacologic inhibition. This pattern was seen in AML cell lines MONOMAC-6 and MOLM-13, as well as in the non-AML cell line HEK293T. Moreover, we do not find an essential oncogenic role for FTO in AML cells lines. Instead, we find that FTO depletion does not impair AML cell viability, and the small-molecule FTO inhibitor FB23-2 is cytotoxic even in FTO-deficient cells, indicating that its toxicity occurs through an FTO-independent mechanism of action. In contrast, FTO depletion caused a robust increase in N6,2’-O-dimethyladenosine (m6Am) in snRNAs, consistent with m6Am being a target of FTO. Together, these findings argue against the model that FTO functions as an “m6A eraser” in AML and caution against attributing the effects of FTO depletion and FTO inhibitors to decreased m6A demethylation.

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FTO depletion does not alter m6A stoichiometry in AML mRNA: a reassessment using direct RNA nanopore sequencing (CROWN-seq data)

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Project description:FTO, an N6-methyladenosine demethylase, has emerged as a promising target for the treatment of specific acute myeloid leukemia (AML) subtypes. Here, we investigate the antiproliferative effects of the FTO inhibitor FB23-2 in leukemia. We demonstrate that FB23-2 potently inhibits proliferation across both AML and CML cell lines, irrespective of their responsiveness to FTO depletion. Interestingly, FB23-2 induces cell cycle arrest without a concurrent increase in m6A levels, suggesting an alternative mechanism of action.

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Recruitment of the m6A/Am demethylase FTO to target RNAs by the telomeric zinc finger protein ZBTB48 [iCLIP-seq]

Project description:Fat mass and obesity-associated protein (FTO) can remove both the N6-methyladenosine (m6A) and N6, 2′-O-dimethyladenosine (m6Am) methylation marks that function in multiple aspects of posttranscriptional regulation. Here, we demonstrate that Zbtb48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of Zbtb48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. Zbtb48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which Zbtb48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.

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Recruitment of the m6A/Am demethylase FTO to target RNAs by the telomeric zinc finger protein ZBTB48 [RNA-seq]

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Project description:Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays a critical oncogenic role in various cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in clinical patients of HCC and presents as a poor prognostic factor. Genetic depletion of FTO dramatically attenuated HCC progression in vivo. Pharmacological inhibition of FTO by FB23/FB23-2 remarkably suppressed the proliferation and migration of HCC cell lines in vitro, as well as inhibiting the HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decreased ERBB3 resulted in inhibited Akt-mTOR signaling that subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 abolished the organization of the tubulin cytoskeleton, while enforced expression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrated that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells, and highlights the broad potential of FTO inhibitors for targeting HCC.

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Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression [RNA-seq]

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