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

Camera, Francesco; Romero-Camarero, Isabel; Revell, Bradley; Amaral, Fabio; Sinclair, Oliver; Simeoni, Fabrizio; Stojic, Lovorka; Somervaille, Tim C. P.

doi:10.1016/j.isci.2023.107319

Cited by 7 publications

(3 citation statements)

References 50 publications

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“…For example, our data show that Irx3 controls genes in the Wnt/β-catenin and Hippo signaling pathways in preadipocytes, and these pathways have been shown by others to also be regulated by Irx3 and/or Irx5 in kidney development [41]. Thus our data may help understand how IRX3 mediates its effects in several other conditions in which IRX3 has been implicated, including type 2 diabetes [10], metabolic inflammation [42], fertility [43], neurogenesis [44,45], glioblastoma [46], acute myeloid leukemia [47][48][49][50], microvascularization [51] and heart development and function [52][53][54][55][56][57].…”

Section: Discussionsupporting

confidence: 58%

Mechanisms of theFTOlocus association with obesity: Irx3 controls a sumoylation-dependent switch between adipogenesis and osteogenesis

Bjune,

Laber,

Lawrence-Archer

et al. 2023

Preprint

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Background: IRX3 is implicated in genetic predisposition to obesity via theFTOvariant locus.IRX3showsFTOrisk allele-dependent upregulation specifically during early adipogenesis, leading to a shift from energy-dissipation to fat storage in mature adipocytes. However, how changes inIRX3expression at one developmental stage affect cellular phenotype at a later stage remains unclear. We here hypothesize that IRX3 regulates adipocyte development via transcriptional modulation of epigenetic reprogramming factors. Methods: We combined ChIP-, ATAC- and RNA-sequencing to map direct Irx3 target genes in regions of open chromatin during early adipogenesis of wild-type andIrx3-KO preadipocytes. Gene ontology analyses was performed to identify significantly enriched biological pathways. Denaturing western blotting was used to assess sumoylation levels, and the inhibitor ML-792 was used to specifically block sumoylation. Luciferase assays were performed to estimate effects of ML-792 on Pparγ activity. Bodipy lipid staining, immunofluorescence and qPCR were employed to assess adipogenic differentiation in 3D culture. Alkaline phosphatase and Alizarine Red S staining, as well as immunofluorescence and qPCR were used to assess osteogenic differentiation in 3D culture. Results: We identified more than 300 Irx3 binding sites in preadipocytes, and these were almost exclusively restricted to promoter regions, with a strong enrichment of genes related to sumoylation, histone modifications and chromatin remodeling. Genes from every step of the sumoylation cycle were bound by Irx3 and differentially expressed in response toIrx3-KO, leading to increased global sumoylation levels in the KO cells. Irx3 ablation and elevated sumoylation inhibited Pparγ activity and adipogenic differentiation in preadipocytes, both of which could be restored by pharmacological inhibition of sumoylation. The Irx3-KO cells demonstrated reduced epigenetic suppression against osteogenesis, resulting in increased osteogenesis in 3D culture. Finally, osteogenesis induced by Irx3 ablation could partially be reversed by inhibition of sumoylation. Conclusions: Our study has uncovered IRX3 as a novel upstream regulator of sumoylation, and a potent controller of epigenetic regulators, both directly and indirectly via suppressing global sumoylation levels. This study indicates that theFTOlocus promotes obesity via IRX3-mediated suppression of sumoylation, which promotes adipogenic commitment and differentiation through epigenetic programming.

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Section: Discussionsupporting

confidence: 58%

Mechanisms of theFTOlocus association with obesity: Irx3 controls a sumoylation-dependent switch between adipogenesis and osteogenesis

Bjune,

Laber,

Lawrence-Archer

et al. 2023

Preprint

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“…5). We thus demonstrate a new somatically acquired mechanism of IRX3 activation initiated through somatic deletions of FTO intron 8, distinct from recent findings in acute myeloid leukemia (AML) describing an intronic long noncoding RNA in FTO that regulates IRX3 expression (44). Together, these findings add to the complex regulatory relationship between the FTO and IRX3 genes first identified through the discovery of obesity-associated germline variants (45,46).…”

Section: Discussionmentioning

confidence: 47%

Focal Deletions of a Promoter Tether Activate theIRX3Oncogene in T Cell Acute Lymphoblastic Leukemia

Rahman,

Bloye,

Farah

et al. 2024

Preprint

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Oncogenes can be activated in cis through multiple mechanisms including enhancer hijacking events and noncoding mutations that create enhancers or promoters de novo. These paradigms have helped parse somatic variation of noncoding cancer genomes, thereby providing a rationale to identify noncanonical mechanisms of gene activation. Here we describe a novel mechanism of oncogene activation whereby focal copy number loss of an intronic element within the FTO gene leads to aberrant expression of IRX3, an oncogene in T cell acute lymphoblastic leukemia (T-ALL). Loss of this CTCF bound element downstream to IRX3 (+224 kb) leads to enhancer hijack of an upstream developmentally active super-enhancer of the CRNDE long noncoding RNA (-644 kb). Unexpectedly, the CRNDE super-enhancer interacts with the IRX3 promoter with no transcriptional output until it is untethered from the FTO intronic site. We propose that promoter tethering of oncogenes to inert regions of the genome is a previously unappreciated biological mechanism preventing tumorigenesis.

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“…Although we do not know the mechanism underlying this increase in enhancer activity in Me3 HIST1 high patients, it is interesting to note that the two genes FOXC1 et IRX5, which check all the boxes (direct targets of NPM1 mut , strong correlation of H3K27ac levels and expression in Me3 HIST1 high ) are coregulated with GATA2 in AMLs. This coregulation may pass through the TAD domain associated with an intron of the FTO (fat mass and obesity-associated) gene on chromosome 16 47 . One of the interesting candidates is the high expression, coupled with H3K27ac accumulation, in the transcription factor FOXC1 in Me3 HIST1 high .…”

Section: Discussionmentioning

confidence: 99%

Epigenenomic and transcriptomic characterization ofNPM1-mutated CN-AML subtypes

N’Guyen,

Tellez-Quijorna,

Vernerey

et al. 2024

Preprint

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Cytogenetic normal AML with NPM1 mutations forms a distinct AML entity, associated with an intermediate prognosis and a heterogeneous response to treatment. We previously described an epigenetic biomarker, defined by the level of H3K27me3 on 70kb of the HIST1 cluster in patient blast DNA. This epigenetic mark separates cytogenetically normal NPM1mut AML into two groups of patients differing in their survival rate following chemotherapy. To better characterize the influence of the biomarker on disease progression, we performed transcriptomic and histone mark profiling on patient blasts according to the level of H3K27me3 HIST1. Our integrated analysis revealed that the two groups of patients display differences in terms of transcriptomic, chromatin landscape and cell surface markers, which could explain the clinical difference. Our profiling revealed novel targets and therefore constitutes an (epi)transcriptomic resource for NPM1 AML. It also highlights the power of epigenetic profiling to dissect the heterogeneity of a single AML genetic entity.

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

Cited by 7 publications

References 50 publications

Mechanisms of theFTOlocus association with obesity: Irx3 controls a sumoylation-dependent switch between adipogenesis and osteogenesis

Mechanisms of theFTOlocus association with obesity: Irx3 controls a sumoylation-dependent switch between adipogenesis and osteogenesis

Focal Deletions of a Promoter Tether Activate theIRX3Oncogene in T Cell Acute Lymphoblastic Leukemia

Epigenenomic and transcriptomic characterization ofNPM1-mutated CN-AML subtypes

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