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HOTTIP reinforces CTCF-defined TAD boundaries by forming R-loops to drive Wnt/b-catenin target gene expression in AML leukemogenesis

ABSTRACT: HOTTIP lncRNA is highly expressed in acute myeloid leukemia (AML) patients carrying MLL rearrangement and NPM1c+ mutations, and positively correlates with poor patient survival by facilitating formation of leukemic-specific topologically associated domains (TADs) to drive leukemic transcription program. However, the direct mechanism through which HOTTIP accesses and regulates leukemic genome topology remains unknown. Here, we showed that HOTTIP directly interacts and regulates a fraction of CTCF binding sites (CBSs) including key WNT/b-catenin target loci in the AML genome by forming R-loop structure that reinforces the CTCF boundary, WNT/b-catenin TADs and gene transcription. Importantly, either deleting CBSs or targeting RNaseH to eliminate R-loop structure in boundaries of the Wnt/b-catenin TADs resulted in inhibited Wnt target promoter interactomes and Wnt target expression, and mitigation of leukemogenesis of PDX mouse models with aberrant HOTTIP expression. Thus, HOTTIP reinforces CTCF-defined TAD boundaries by forming R-loops to drive Wnt/b-catenin aberration and pathogenesis of MLL-rearranged/NPM1c+ AML.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE165049 | GEO | 2022/02/18

REPOSITORIES: GEO

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NPM1 mutation reprograms leukemic transcription network via reshaping TAD topology

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2023-08-09 | GSE208022 | GEO

HOTTIP reinforces CTCF-defined TAD boundaries by forming R-loops to drive Wnt/b-catenin target gene expression in AML leukemogenesis

Project description:HOTTIP reinforces CTCF-defined TAD boundaries by forming R-loops to drive Wnt/b-catenin target gene expression in AML leukemogenesis

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A Preclinical Model of Human Acute Myeloid Leukemia with an Autologous Immune System for Studying Mechanisms of Tumorigenesis and Immunotherapy

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Activation of HOTTIP lncRNA perturbs HSC function leading to AML like disease

Project description:We found that posterior HOXA-associated HOTTIP lncRNA is aberrantly activated in MLL-rearranged AMLs and required for the posterior HOXA chromatin structure and gene expression. Knock-out of HOTTIP attenuates leukemic progressions of the transplanted humanized AML mice by blocking posterior HOXA-associated AML gene expression programs while the dCas-VP160 mediated reactivation of HOTTIP restores HOXA locus chromatin structure and HOXA9-A13 gene expression in the CBS7/9 boundary depleted AML cells. Finally, transgenic expression of HOTTIP lncRNA in mouse bone marrow hematopoietic cells resulted in perturbation of the balance of HSC self-renewal and differentiation and development of AML like disease by aberrant altering HOXA associated chromatin structure and transcription program. Thus, HOTTIP lncRNA acts as oncogene to reprogram leukemic associated chromatin and gene transcription.

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Cytoplasmic NPM1 maintains the leukemic state through HOX expression [ChIP-seq] 

Project description:NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c). NPM1 mutations are founding genetic lesions, however it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in downregulation of homeobox (HOX) genes, and differentiation and cell growth arrest of AML cells. Additionally, we show that HOX downregulation is the earliest transcriptional event following the loss of NPM1c from the cytoplasm, preceding and promoting differentiation. Finally, we show that XPO1 inhibition efficiently relocalizes NPM1c to the nucleus, enables differentiation and prolongs survival of Npm1c+ leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.

2018-08-06 | GSE111179 | GEO

Cytoplasmic NPM1 maintains the leukemic state through HOX expression [RNA-seq]  

2018-08-06 | GSE111178 | GEO

Characterisation of the Beta-Catenin cytoplasmic/nuclear interactome in leukaemia cells

Project description:Canonical Wnt/B-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia (AML) patients; however, some patients exhibit little or no β-catenin nuclear-localization even where cytosolic B-catenin is abundant. Differential propensity for nuclear-localized β-catenin is also observed in cell lines. To investigate the factors mediating the nuclear-localization of B-catenin we carried out a nuclear/cytoplasmic proteomic analysis of the B-catenin interactome in myeloid leukemia cells. From this we identified hundreds of putative novel B-catenin-interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear B-catenin, K562/HEL) versus Wnt-unresponsive cells (low nuclear B-catenin, ML1) suggested the established interactor, LEF1, is a key factor mediating the nuclear-localization of B-catenin in myeloid leukemia. The relative levels of nuclear LEF1 and B-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF1 knockdown inhibited B-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF1 overexpression was able to promote both nuclear-localization and B-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This study is the first to present a B-catenin interactome in hematopoietic cells and reveals LEF1 as a critical regulator of canonical Wnt signaling in myeloid leukemia.

2019-01-11 | PXD009305 | Pride

A coordinated function of lncRNA HOTTIP and miRNA-196b underpinning leukemogenesis by targeting Fas signaling

Project description:MicroRNAs (miRNAs) may modulate more than 60% of human coding genes and act as negative regulators, while long non-coding RNAs (lncRNAs) regulate gene expression on multiple levels by interacting with chromatin, functional proteins, and RNAs such as mRNAs and microRNAs. However, the crosstalk between lncRNA HOTTIP and miRNAs in leukemogenesis remains elusive. Using combined integrated analyses of global miRNA expression profiling and state-of-the-art genomic analyses of chromatin such as ChIRP seq., (genome wide HOTTIP binding analysis), ChIP-seq., and ATAC-seq., we found that miRNA genes are directly controlled by HOTTIP. Specifically, the HOX cluster miRNAs (miR-196a, miR-196b, miR-10a and miR-10b), located cis & trans, were most dramatically regulated and significantly decreased in HOTTIP–/– AML cells. HOTTIP bound to the miR- 196b promoter, and HOTTIP deletion reduced chromatin accessibility and enrichment of active histone modifications at HOX cluster associated miRNAs in AML cells, while reactivation of HOTTIP restored miR gene expression and chromatin accessibility in the CTCF-boundary-attenuated AML cells. Inactivation of HOTTIP or miR-196b promotes apoptosis by altering the chromatin signature at the FAS promoter and increasing FAS expression. Transplantation of miR-196b knockdown MOLM13 cells in NSG mice increased overall survival compared to wild-type cells. Thus, HOTTIP remodels the chromatin architecture around miRNAs to promote their transcription, consequently repressing tumor suppressors and promoting leukemogenesis.

2022-09-14 | GSE182601 | GEO

Low affinity CTCF binding drives transcriptional regulation whereas high affinity binding encompasses architectural functions.

Project description:This SuperSeries is composed of the SubSeries listed below. CTCF is a DNA-binding protein which plays critical roles in chromatin structure organization and transcriptional regulation; however, little is known about the functional determinants of different CTCF binding sites (CBS). Using a conditional mouse model, we have identified one set of CBSs that are lost upon CTCF depletion (lost CBSs) and another set that persists (retained CBSs). Retained CBSs are more similar to the consensus CTCF binding sequence and usually span tandem CTCF peaks. Lost CBSs are enriched at enhancers and promoters and associate with active chromatin marks and higher transcriptional activity. In contrast, retained CBSs are enriched at TAD and loop boundaries. Integration of ChIP-seq and RNA-seq data has revealed that retained CBSs are located at the boundaries between distinct chromatin states, acting as chromatin barriers. Our results provide evidence that transient, lost CBSs are involved in transcriptional regulation, whereas retained CBSs are critical for establishing higher-order chromatin architecture.

2023-02-10 | GSE207640 | GEO

Comprehensive comparison and biologic activity of novel therapeutic agents in NPM1 mutated Acute Myeloid Leukemia (AML)

Project description:Acute Myeloid Leukemia (AML) is frequently associated with mutations of NPM1 (NPM1c+) and even if considered to be of better prognosis for younger patients, relapse is frequent and outcome remains poor for elder patients with a need for novel treatment strategies. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) induce proteasomal degradation of NPM1c protein, NPM1 nuclear re localization, differentiation and apoptosis in NPM1c+ cells and blast clearance in relapsed/refractory AML patients. In line, the XPO1 inhibitor Selinexor showed similar results in vitro associated with down regulation of a specific HOX gene signature. BET inhibitors (BETi) OTX015 (MK-8628) and JQ1 yield antileukemic activity and here we demonstrate their effects in NPM1c+ leukemia cells compared to ATO+ATRA and Selinexor. Compared to ATO+ATRA and Selinexor, BRDi induced TP53 independent apoptosis, differentiation, proteasomal NPM1c degradation and nuclear relocalization in NPM1c+ OCI-AML3 cell line and to different extend in patient derived blast cells. As ATO+ATRA and Selinexor had significant biological activity in NPM1c+ cell line IMS-M2, these cells were resistant to BETi exposure, except for nuclear re localization of NPM1 which is a general phenomenon upon treatment with all three drug types. Gene profiling revealed that BRDi downregulate a BRD specific core gene signature in OCI-AML3 and IMS-M2 cells but IMS-M2 cells yield a transcriptional resistance signature including upregulation of the Wnt/beta-catenin pathway. HOX gene clusters in OCI-AML3 cells and IMS-M2 cells are heterogeneously regulated by BETi and are down regulated by ATO+ATRA in line with results reported for Selinexor treatment. Taken together, our preclinical results encourage clinical testing of ATO+ATRA, Selinexor and BRDi in NPM1c+ AML patients.

2020-06-01 | GSE146362 | GEO

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