High expression of an intragenic long noncoding RNA misinterpreted as high FTO oncogene expression in NPM1 mutant acute myeloid leukemia

Arza-Apalategi, Saioa; Heuts, Branco M. H.; Dooijes, Meike T. M.; Gilissen, Daan; Heijden, Adrian J. P. van der; Jansen, Joop H.; Martens, Joost H.A.; Reijden, Bert A. van der

doi:10.1038/s41375-023-01844-w

Cited by 2 publications

(2 citation statements)

References 16 publications

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“…Such a mechanism has previously been postulated for the activity of the long non-coding RNA LncHSC-2 in hematopoietic stem cells. 32 Recently, Arza-Apalategi and colleagues 33 also noted the association of FTO -lncRNA expression (which they termed IFEX9) with the presence of a higher level of differentiation block in NPM1-mutated cases within the Beat AML cohort, although this was not linked functionally to either IRX3 or HOXA gene expression.…”

Section: Discussionmentioning

confidence: 99%

Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO

Camera¹,

Romero-Camarero²,

Revell³

et al. 2023

iScience

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Section: Discussionmentioning

confidence: 99%

Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO

Camera¹,

Romero-Camarero²,

Revell³

et al. 2023

iScience

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“…A recent study identifies that the high expression of FTO in NPM1 mutant AML patients may be attributed to an intragenic long noncoding RNA within FTO. It is a result of intragenic transcription activation occurring in the final intron of FTO, induced by a non-random epigenetic event [ 24 ]. R-2-hydroxyglutarate, produced by mutant isocitrate dehydrogenase 1/2 (IDH1/2), inhibits the proliferation of leukemic cells by suppressing the demethylase activity of FTO and its downstream CEBPA/MYC-relevant pathway [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

A novel AML1-ETO/FTO positive feedback loop promotes leukemogenesis and Ara-C resistance via stabilizing IGFBP2 in t(8;21) acute myeloid leukemia

Zhou,

Li,

Wang

et al. 2024

Exp Hematol Oncol

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Background t(8;21)(q22;q22) is one of the most frequent chromosomal abnormalities in acute myeloid leukemia (AML), leading to the generation of the fusion protein AML1-ETO. Despite t(8;21) AML being considered as a subtype with a favorable prognosis, approximately 30–50% of patients experience drug resistance and subsequent relapse. N6-methyladenosine (m6A) is demonstrated to be involved in the development of AML. However, the regulatory mechanisms between AML1-ETO and m6A-related enzymes and the roles of dysregulated m6A modifications in the t(8;21)-leukemogenesis and chemoresistance remain elusive. Methods Chromatin immunoprecipitation, dual-luciferase reporter assay, m6A-qPCR, RNA immunoprecipitation, and RNA stability assay were used to investigate a regulatory loop between AML1-ETO and FTO, an m6A demethylase. Gain- and loss-of-function experiments both in vitro and in vivo were further performed. Transcriptome-wide RNA sequencing and m6A sequencing were conducted to identify the potential targets of FTO. Results Here we show that FTO is highly expressed in t(8;21) AML, especially in patients with primary refractory disease. The expression of FTO is positively correlated with AML1-ETO, which is attributed to a positive regulatory loop between the AML1-ETO and FTO. Mechanistically, AML1-ETO upregulates FTO expression through inhibiting the transcriptional repression of FTO mediated by PU.1. Meanwhile, FTO promotes the expression of AML1-ETO by inhibiting YTHDF2-mediated AML1-ETO mRNA decay. Inactivation of FTO significantly suppresses cell proliferation, promotes cell differentiation and renders resistant t(8;21) AML cells sensitive to Ara-C. FTO exerts functions by regulating its mRNA targets, especially IGFBP2, in an m6A-dependent manner. Regain of Ara-C tolerance is observed when IGFBP2 is overexpressed in FTO-knockdown t(8;21) AML cells. Conclusion Our work reveals a therapeutic potential of targeting AML1-ETO/FTO/IGFBP2 minicircuitry in the treatment for t(8;21) patients with resistance to Ara-C.

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High expression of an intragenic long noncoding RNA misinterpreted as high FTO oncogene expression in NPM1 mutant acute myeloid leukemia

Cited by 2 publications

References 16 publications

Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO

Differentiation block in acute myeloid leukemia regulated by intronic sequences of FTO

A novel AML1-ETO/FTO positive feedback loop promotes leukemogenesis and Ara-C resistance via stabilizing IGFBP2 in t(8;21) acute myeloid leukemia

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